Practice Guidelines in Oncology - Non-Small Cell Lung Cancer

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NCCN Clinical Practice Guidelines in Oncology™

Non-Small CellLung Cancer

V.2.2010

www.nccn.org

Version 2.2010, 03/05/10 © 2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Practice Guidelinesin Oncology – v.2.2010

Guidelines Index

NSCL Table of Contents

Staging, Discussion, ReferencesNon-Small Cell Lung CancerNCCN®

NCCN Non-Small Cell Lung Cancer Panel MembersDavid S. Ettinger, MD/Chair †The Sidney Kimmel Comprehensive CancerCenter at Johns Hopkins

Wallace Akerley, MDHuntsman Cancer Institute at the University ofUtah

Gerold Bepler, MD, PhDH. Lee Moffitt Cancer Center & ResearchInstitute

Matthew G. Blum, MD

Andrew Chang, MDUniversity of Michigan Comprehensive CancerCenter

Richard T. Cheney, MD

Lucian R. Chirieac, MDDana-Farber/Brigham and Women's CancerCenter

†

†

¶Robert H. Lurie Comprehensive Cancer Centerof Northwestern University

¶

Roswell Park Cancer Institute

Thomas A. D’Amico, MD ¶Duke Comprehensive Cancer Center

Todd L. Demmy, MD ¶Roswell Park Cancer Institute

Apar Kishor P. Ganti, MD †UNMC Eppley Cancer Center at The NebraskaMedical Center

Ramaswamy Govindan, MD †Siteman Cancer Center at Barnes-JewishHospital and Washington University School ofMedicine

Frederic W. Grannis, Jr., MD ¶City of Hope Comprehensive Cancer Center

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Raymond U. Osarogiagbon, MDSt. Jude Children’s Research Hospital/Universityof Tennessee Cancer Institute

Gregory A. Otterson, MD †Arthur G. James Cancer Hospital & Richard J.Solove Research Institute at The Ohio StateUniversity

Jyoti D. Patel, MD ‡Robert H. Lurie Comprehensive Cancer Center ofNorthwestern University

Katherine M Pisters, MD ¶ †The University of Texas M. D. Anderson CancerCenter

Karen Reckamp, MD, MS †City of Hope Comprehensive Cancer Center

†Memorial Sloan-Kettering Cancer Center

The University of Texas M. D. Anderson CancerCenter

†

¶Dana-Farber/Brigham and Women's CancerCenter

¶Fred Hutchinson Cancer Research Center/SeattleCancer Care Alliance

Stephen C. Yang, MD ¶The Sidney Kimmel Comprehensive CancerCenter at Johns Hopkins

Gregory J. Riely, MD, PhD

Eric Rohren, MD, PhD

George R. Simon, MDFox Chase Cancer Center

Scott J. Swanson, MD

Douglas E. Wood, MD

†

ф

Thierry Jahan, MD †

Mohammad Jahanzeb, MDSt. Jude Children’s Research Hospital/University ofTennessee Cancer Institute

David H. Johnson, MDVanderbilt-Ingram Cancer Center

Anne Kessinger, MDUNMC Eppley Cancer Center at The NebraskaMedical Center

Ritsuko Komaki, MDThe University of Texas M. D. Anderson CancerCenter

Feng-Ming Kong, MD, PhDUniversity of Michigan Comprehensive CancerCenter

Mark G. Kris, MD †

UCSF Helen Diller Family Comprehensive CancerCenter

†

†

†

§

§

Memorial Sloan-Kettering Cancer Center

Lee M. Krug, MD †Memorial Sloan-Kettering Cancer Center

Quynh-Thu Le, MD §Stanford Comprehensive Cancer Center

Inga T. Lennes, MD †Massachusetts General Hospital Cancer Center

Renato Martins, MD †Fred Hutchinson Cancer Research Center/SeattleCancer Care Alliance

Janis O’Malley, MDUniversity of Alabama at BirminghamComprehensive Cancer Center

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*

† Medical Oncology¶ Surgery/Surgical oncology§ Radiation oncology/

Pathology

‡ Hematology/Hematology oncology

Radiotherapy

*Writing Committee Member�

ф Diagnostic/

Interventional Radiology

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NCCN Guidelines Panel Disclosures

*

http://www.nccn.org/disclosures/panel_list.asp?ID=40



Guidelines Index



Table of Contents

Evaluation and Treatment:

NCCN Non-Small Cell Lung Cancer Panel Members

Lung Cancer Prevention and Screening (PREV-1)

Initial Evaluation and Clinical Stages (NSCL-1)

Stage 0 (Tis) and Occult (TX, N0, M0) (NSCL-16

Stage I (T1-2, N0) and Stage II (T1-2, N1) (NSCL-2

Stage IIB (T3, N0) and Stage IIIA, IIIB (T3-4, N1) (NSCL-4

Stage IIIA (T1-3, N2) and Separate Pulmonary Nodules (NSCL-6

Stage IIIB (T1-3, N3) (NSCL-9

Stage IIIB (T4 extension, N2-3) and Stage IV (pleural or pericardial effusion) (NSCL-10

Stage IV (M1b: solitary site and disseminated) (NSCL-11

Principles of Pathologic Review (NSCL-A

Principles of Surgical Therapy (NSCL-B

Principles of Radiation Therapy (NSCL-C

Chemotherapy Regimens for Adjuvant Therapy (NSCL-D

Chemotherapy Regimens Used with Radiation Therapy (NSCL-E)

Systemic Therapy for Advanced or Metastatic Disease (NSCL-F

Cancer Survivorship Care (NSCL-G

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Surveillance (NSCL-12

Second Lung Primary (NSCL-16)

Therapy for Recurrence and Metastasis (NSCL-12

Guidelines Index

Print the Non-Small Cell Lung Cancer Guideline

)

)

These guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.Any clinician seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinicalcircumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network makes no representations nor warrantiesof any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. Theseguidelines are copyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may notbe reproduced in any form without the express written permission of NCCN. ©2010.

Clinical Trials:

Categories of Evidence andConsensus:NCCN

All recommendationsare Category 2A unless otherwisespecified. See

Thebelieves that the best managementfor any cancer patient is in a clinicaltrial. Participation in clinical trials isespecially encouraged.

NCCN

NCCN Categories ofEvidence and Consensus

Summary of Guidelines Updates

Click here to find a clinical

trial at an NCCN Center

For help using thesedocuments, please click here

Staging

Discussion

References

http://www.nccn.org/clinical_trials/physician.html



Guidelines Index



Summary of the Guidelines updates

UPDATES

Summary of the changes in the 1.2010 version of the Non-Small CellLung Cancer guidelines from the 2.2009 version include:

Footnote “b”- definition of peripheral changed from “outer half of

lung” to “outer third of lung.”

Clinical staging updated as per the updated staging from IASLC.

Stage IA (peripheral T1ab, N0) - clarification was added that thebronchoscopy is preferred intraoperatively.”Endobronchial ultrasound (EBUS)” was added as an option inpretreatment evaluation with a category 2B designation.Patients medically inoperable after negative mediastinal nodes, theoptions of “Definitive RT” or “Limited resection” were added.

Footnote “h” modified to define “high-risk” patients as “poorlydifferentiated tumors, vascular invasion, wedge resection, minimalmargins, tumors > 4 cm, visceral pleural involvement, Nx.”Stage IA, margins negative - chemotherapy removed as atreatment option.Stage IA, margins positive - reresection listed as “preferred.” Theoption of consolidation chemotherapy after resection or afterchemoradiation was removed.Stage IB, margins negative - chemotherapy qualified as for “high-risk patients” with a footnote describing the high-risk patients.Stage IIA, IIB, margins negative, adverse factors - Chemoradiationrecommendation changed from a 2B designation to a category 3designation.Stage IIIA, margins negative - “mediastinal” deleted before RT.

Separate pathway created for superior sulcus tumors with T3

invasion as these tumors are resectable.

Superior sulcus tumors with T4 invasion have treatment options

listed for marginally resectable and unresectable disease.

Chest wall, proximal airway, mediastinum - RT removed as an

initial treatment option. Margins negative - chemotherapy in the

adjuvant setting clarified as “if not given as initial treatment.”

Previous stage IIIB (T4, N0-1) changed to “Separate pulmonary

nodules and/or pleural effusions (stage IIB, IIIA, IV).”

T1-3, N0-1, resectable - “or lymph node sampling” added after“mediastinal lymph node dissection.” Margins negative -chemoradiation + chemotherapy in the adjuvant setting removed.“RT” added to chemotherapy as a sequential therapy option.

Separate pulmonary nodules, same lobe or ipsilateral lung - margin

status added after surgery with treatment recommendations.

Separate pulmonary nodules, contralateral lung - “concurrent”

chemoradiation changed to “induction” chemoradiation. Margins

negative after surgery, “± RT (if not given)” added to adjuvant

chemotherapy and “Observation” added as a option.

Stage IIIA (T4, N0-1) unresectable (without effusion) - Consolidation

chemotherapy changed from a category 2B to a category 3

designation.

Metastatic site of the brain, “stereotactic radiosurgery (SRS)

(category 2B)” added as an option in addition to resection + WBRT.

Metastatic site of the adrenal, resection changed to “local therapy.”

“PET or brain MRI is not indicated for routine follow-up” added to

the Surveillance recommendations.

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Footnote “s” added to define “select patients”. “The administration

of chemotherapy in the adjuvant setting depends on the type of

neoadjuvant therapy and the patient’s tolerance.”

”SRS” added as a treatment option with a category 2B designation

for T1-2, N0-1 or T3, N0 after initial treatment.

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NSCL-1

NSCL-2

NSCL-8

NSCL-3:

NSCL-5

NSCL-6

NSCL-7

NSCL-11

NSCL-12

The 2.2010 version of the Non-Small Cell Lung Cancer guidelines represents the addition of the Discussion section correspondent to thechanges in the algorithm.



Guidelines Index


Staging, Discussion, ReferencesNon-Small Cell Lung Cancer®

NCCNSummary of the Guidelines updates

UPDATES

Summary of the changes in the 1.2010 version of the Non-Small Cell Lung Cancer guidelines from the 2.2009 version include:

·The first bullet under BAC was removed noting that there is ·Cetuximab, vinorelbine, cisplatin was changed from a category 2A increasing attention to BAC due to the association with EGFR to a category 2B designation. mutation.·”Erlotinib” was added as a treatment option for patients who are

positive for the EGFR mutation. Footnotes “ee” and “gg” were ·Principles of Surgical Therapy page updated.added to include the supporting references.

·Footnote “z” was added to note that bevacizumab should be given ·Principles of Radiation Therapy pages updated.until progression.

·Footnote “aa” was modified to remove the criterion of “no ·Pemetrexed and cisplatin regimen added to “Other acceptable untreated CNS metastases”.

cisplatin-based regimens” for adenocarcinoma, large cell carcinoma ·Footnote “bb” was added to clarify that pemetrexed is not and NSCLC NOS (without specific histologic subtype).recommended for squamous histology.

·Footnote “dd” was modified by removing the criteria.Advanced Disease·Footnote “ff” was added to emphasize that full-dose cisplatin

should be given selectively for PS 2 patients. ·Third bullet added emphasizing importance of histology.First-line therapy

·Tumor response evaluation after cycle 1 was clarified by adding “if ·“Bevacizumab should be given until disease progression” added to clinically indicated.” The category 3 designation was removed. the first bullet.

·Tumor response evaluation was added after cycle 2. ·There is a new third bullet, “Erlotinib is indicated for patients with a ·The category 2B designation was removed from continuation of positive EGFR mutation.”

therapy until progression.Maintenance therapy section added.·Continuation maintenance was added with the options of Second-line therapybevacizumab and cetuximab as category 1 designations. ·Pemetrexed bullet modified, noting that it was “superior” to Pemetrexed remains an option with a category 2B designation.

·Switch maintenance was added with the options of erlotinib with a docetaxel with less toxicity “in patients with adenocarcinoma and category 2B designation or docetaxel with a category 3 large cell carcinoma.”designation. Pemetrexed remains an option with a category 2B and designation. ·Staging updated as per the IASLC recommendations.

·Observation with close follow-up was also added as an option for patients with responsive or stable disease.

·”Platinum-doublet therapy” was added as an option for second-line therapy with a category 2B designation if the patient received erlotinib as first-line therapy.

·Footnote “jj” was clarified for patients “with the EGFR mutation.”

NSCL-A 1 of 2NSCL-13

NSCL-B

NSCL-C

NSCL-D

NSCL-F 1 of 3

NSCL-14

NSCL-F 2 of 3

ST-1 ST-2

NSCL-15



Guidelines Index



LUNG CANCER PREVENTION AND SCREENING

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Lung cancer is a unique disease in that the etiologic agent is an industry. More than 90% of cases are caused by voluntary or

involuntary (second hand) cigarette smoking. Reduction of lung cancer mortality will require effective public health policies to prevent

initiation of smoking, U.S. Food and Drug Administration (FDA) oversight of tobacco products and other tobacco control measures.

Reports from the Surgeon General on both active smoking

( ) and second-hand smoke show that both cause lung

cancer. The evidence shows a 20% to 30% increase in the risk of lung cancer from second-hand smoke exposure associated with living

with a smoker ( ). Every person should be informed of

the health consequences, addictive nature and mortal threat posed by tobacco consumption and exposure to tobacco smoke and

effective legislative, executive, administrative or other measures should be contemplated at the appropriate governmental level to

protect all persons from exposure to tobacco smoke. .

Further complicating this problem, the delivery system of lung carcinogens also contains the highly addictive substance, nicotine.

Reduction of lung cancer mortality will require widespread implementation of Agency for Healthcare Research and Quality (AHRQ)

Guidelines ( ) to identify, counsel, and treat patients with nicotine habituation.

Patients who are current or former smokers have significant risk for the development of lung cancer; chemoprevention agents are not

yet established for these patients. When possible, these patients should be encouraged to enroll in chemoprevention trials.

At the present time, the NCCN panel does not recommend the routine use of screening CT as standard clinical practice (category 3).

Available data are conflicting and, thus, conclusive data from ongoing national trials are necessary to define the benefits and risks

associated with screening for lung cancer with low dose CT. The panel recommends that high risk individuals participate in a clinical

trial evaluating CT screening. If a trial is not available or the high risk individual is not eligible for participation in a trial, then the

individual should go to a center of excellence with expertise (in radiology, pathology, cytology, thoracic surgery, and general expertise

in lung cancer treatment) to discuss the potential risks and benefits before having a screening CT. If a screening strategy is used, then

the I-ELCAP screening protocol should be followed.

1-5

2

http://www.cdc.gov/tobacco/data_statistics/sgr/2004/pdfs/executivesummary.pdf

www.surgeongeneral.gov/library/secondhandsmoke/report/executivesummary.pdf

www.who.int/tobacco/framework/final_text/en/

www.ahrq.gov/clinic/cpgsix.htm

http://www.ielcap.org/professionals/docs/ielcap.pdf

PREV-1

1

2

4

5

Henschke CI, Yakelevitz DF, Libby DM, et al. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006;355:1763-71.

Bach PB, Jett JR, Pastorino U, et al. Computed tomography screening and lung cancer outcomes. JAMA 2007;297:953-961.

McMahon PM, Kong CY, Johnson BF, et al. Estimating long-term effectiveness of lung cancer screening in the Mayo CT Screening Study. Radiology 2008;248:278-287.

Jett JR, Midthun DE. Commentary: CT screening for lung cancer--caveat emptor. Oncologist 2008;13(4):439-444.

Mulshine JL. Commentary: lung cancer screening--progress or peril. Oncologist 2008;13(4):435-438.

3

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.



Guidelines Index



PATHOLOGIC

DIAGNOSIS OF NSCLC

INITIAL EVALUATION CLINICAL STAGE

Non-Small Cell

Lung Cancer

(NSCLC)

a

b

c

.

Based on the CT of the chest:Peripheral = outer third of lung.Central = inner two thirds of lung.

For patients considered to have stage IIB and stage III tumors,where more than one treatment modality (surgery, radiation therapy,or chemotherapy) is usually considered, a multidisciplinaryevaluation should be performed.

See Principles of Pathologic Review (NSCL-A)

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Pathology review

H&P (include

performance status

+ weight loss)

CT chest and upper

abdomen, including

adrenals

CBC, platelets

Chemistry profile

Smoking cessation

counseling

a

See PretreatmentEvaluation (NSCL-2)




Stage IIIB (T4 extension, N2-3) on CTc See PretreatmentEvaluation (NSCL-10)




Stage IIIA (T1-3, N2)c See PretreatmentEvaluation (NSCL-6)

See Evaluation(NSCL-16)

Occult TX, N0, M0

See Evaluation(NSCL-16)

Second lung primary


Stage IIIB (T1-3, N3) mediastinal CT positive

Contralateral (lymph nodes 1 cm) or

palpable supraclavicular lymph nodes

c

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NSCL-1



Stage IA, peripheral (T1ab, N0)

Mediastinal CT negative (lymph nodes < 1 cm)

b

Stage I, peripheral (T2a, N0); central (T1ab-T2a, N0);

stage II (T1ab-T2ab, N1; T2b, N0); stage IIB (T3, N0)

Mediastinal CT negative (lymph nodes < 1 cm)

bb

Separate pulmonary nodule(s) and/or

pleural effusion (Stage IIB, IIIA, IV)

Stage IV (M1a) (pleural

or pericardial effusion)

c

Stage IV (M1b)

Solitary metastasis with resectable lung lesion

Stage IV (M1b)

Disseminated metastases

Stage IIB (T3, N0);

Stage IIIA (T3-4, N1)

c



Guidelines Index



PRETREATMENT EVALUATIONeCLINICAL ASSESSMENT

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PFTs (if not previously done)

Bronchoscopy (intraoperative

preferred)

Mediastinoscopy (category 2B)

EBUS if appropriate (category 2B)

PET/CT scand

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Bronchoscopy

Mediastinoscopy

PET/CT scan

Brain MRI (Stage II only)

EBUS if appropriate (category 2B)d

Positive

mediastinal

nodes

Negative

mediastinal

nodes

dPositive PET/CT scan findings need pathologic or other radiologic confirmation. If PET/CT scan positive in the mediastinum, lymph node status needs pathologicconfirmation.

e .See Principles of Surgical Therapy (NSCL-B)

See Initial Treatmentand AdjuvantTreatment (NSCL-3)

NSCL-2



Operable

Medically

inoperable

Definitive RT

orLimited resection

( )

( )

see NSCL-C

see NSCL-B

SeeStage IIIA (NSCL-7)

Stage IIIB (NSCL-9)or

Stage IA

(peripheral T1ab, N0)

Stage IB (peripheral T2a, N0)

Stage I (central T1ab–T2a, N0)

Stage II (T1ab–2ab, N1; T2b, N0)Stage IIB (T3, N0)



Guidelines Index



Reresection + chemotherapyor

j

i,k,lChemoradiation + chemotherapy

Chemotherapyj (category 1)

Chemotherapy (category 1)orChemoradiation (category 3) + chemotherapy

j

i,k,l

Observe

Reresection (preferred)orChemoradiation (category 2B)orRT (category 2B)

i,k,l

i

Chemoradiation + chemotherapyi,k,l

ADJUVANT TREATMENTFINDINGS AT SURGERY

Margins positive

(R1, R2)f

No adverse

factorsg

Adverse

factorsg

Margins

negative (R0)f

Margins positive

(R1, R2)f

Margins negative (R0)f

Margins positive (R1, R2)f

Margins

negative (R0)f

Surgical

exploration and

resection and

mediastinal lymph

node sampling or

dissection

e

INITIAL TREATMENT

e

f

g

h

i

j

l

.

R0 = no residual tumor, R1 = microscopic residual tumor, R2 = macroscopic residualtumor.

Adverse factors include: inadequate mediastinal lymph node dissection,extracapsular spread, multiple positive hilar nodes, close margins.

High-risk patients are defined by poorly differentiated tumors, vascular invasion,wedge resection, minimal margins, tumors > 4 cm, visceral pleural involvement, Nx.

.

.

For patients with negative margins, most NCCN institutions give sequentialchemotherapy/RT; for patients with positive margins, most NCCN institutionsgive concurrent chemo/RT ± chemotherapy.

k

See Principles of Surgical Therapy (NSCL-B) See Principles of Radiation Therapy (NSCL-C)

See Chemotherapy Regimens for Adjuvant Therapy (NSCL-D)

See Chemotherapy Regimens used with Radiation Therapy (NSCL-E).

ObserveorChemotherapy (category 2B) in high-risk patientsj h

Reresection + chemotherapyorChemoradiation + chemotherapy

j

i,k,l

Margins positive

(R1, R2)f

Margins

negative (R0)f

NSCL-3



Surveillance(NSCL-12)

Chemotherapy (category 1) + RTj i

Stage IIA

(T1ab-T2a, N1)Stage IIB

(T3, N0; T2b, N1)

Stage IA

(T1ab, N0)

Stage IIIA(T1-3, N2)

Stage IB

(T2a, N0);Stage IIA(T2b, N0)



Guidelines Index



dPositive PET/CT scan findings need pathologic or other radiologic confirmation. If PET/CT scan positive in the mediastinum, lymph node status needs pathologicconfirmation.

PRETREATMENT

EVALUATION

Stage IIB (T3, N0)

Stage IIIA (T3-4, N1)

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Bronchoscopy

Mediastinoscopy

Brain MRI

MRI of spine + thoracic inlet

for superior sulcus lesions

abutting the spine or

subclavian vessels

PET/CT scand

CLINICAL EVALUATIONCLINICAL

ASSESSMENT

Metastatic disease See Treatment for Metastasis(NSCL-11)

Proximal airway

or mediastinumSee Treatment (NSCL-5)

Chest wall See Treatment (NSCL-5)

Superior sulcus tumor See Treatment (NSCL-5)

NSCL-4





Guidelines Index



INITIAL TREATMENT ADJUVANT

TREATMENT

CLINICAL

PRESENTATION

Unresectablee

Preoperative

concurrent

chemoradiationi,k,n

Surgery +

chemotherapy

e

j

Definitive

concurrent

chemoradiationi,k,o,p

e

f

i

j

l

m

n

o

p

q

.

R0 = no residual tumor, R1 = microscopic residual tumor, R2 = macroscopicresidual tumor.

.

.

For patients with negative margins, most NCCN institutions give sequentialchemotherapy/RT; for patients with positive margins, most NCCNinstitutions give concurrent chemo/RT ± chemotherapy.

It is sometimes difficult to distinguish between T3 and T4 superior sulcustumors.

In the preoperative chemoradiation setting, a total dose of 45-50 Gy in 1.8 to 2 Gyfractions should be used to treat all volumes of gross disease, although preoperativechemoradiotherapy should be avoided if a pneumonectomy is required to avoid post-operative pulmonary toxicity.

RT should continue to definitive dose without interruption if patient is not a surgicalcandidate.

In the definitive chemoradiation setting, a total dose of 60-70 Gy in 1.8 to 2 Gy fractionsshould be used to treat all volumes of gross disease.

Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resectionfor non-small cell lung carcinomas of the superior sulcus: Initial results of the SouthwestOncology Group trial 9416 (Intergroup trial 0160). J Thorac Cardiovasc Surg2001;121(3):472-483.

k

See Principles of Surgical Therapy (NSCL-B)

See Principles of Radiation Therapy (NSCL-C)



Marginally

resectablee

Preoperative

concurrent

chemoradiationi,k,n

Surgical

reevaluationq

Resectable

UnresectableComplete definitive RT

+ chemotherapy

i

j

NSCL-5

Surgery (preferred)or

e

Concurrent

chemoradiationorChemotherapy

i,k,n

Margins

negative (R0)f

Margins positive

(R1, R2)f

Chemotherapy if not

given as initial treatment

j

Reresection +

chemotherapy

or

j if not


Chemoradiation +

chemotherapy if not


i,k,l

Surgerye




Surgery +

chemotherapy

e

j

Superior sulcus

tumor

(T4 extension, N0-1)

m

Chest wall,

proximal airway or

mediastinum

(T3 invasion, N0-1T4 extension, N0-1)

Superior sulcus

tumor

(T3 invasion, N0-1)

m



Guidelines Index



Stage IIIA

(T1–3, N2)

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PFTs (if not

previously done)

Bronchoscopy

Mediastinoscopy

Brain MRI

MRI of spine, as

clinically indicated

PET/CT scand

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PFTs (if not previously

done)

Bronchoscopy

Pathologic mediastinal

lymph node evaluation

PET/CT scan

Brain MRI

r

d

PRETREATMENT EVALUATIONCLINICAL

ASSESSMENT

MEDIASTINAL BIOPSY FINDINGS

AND RESECTABILITY

N2, N3 nodes negative

N2 nodes positive

N3 nodes positive See Stage IIIB (NSCL-9)

See Treatment (NSCL-7)

See TreatmentT 1-3, N0-1 (NSCL-7)

d

r

Positive PET/CT scan findings need pathologic or other radiologic confirmation. If PET/CT scan positive in themediastinum, lymph node status needs pathologic confirmation.

Methods for evaluation include mediastinoscopy, mediastinotomy, EBUS-FNA, EUS-FNA and CT-guided FNA biopsy.

Metastatic disease See Treatment for Metastasis(NSCL-11)

NSCL-6



Separate pulmonary

nodule(s) and/or

pleural effusions

(Stage IIB, IIIA, IV)

Separate pulmonary

nodule(s), same lobe

or ipsilateral lung

Separate pulmonary

nodule(s),

contralateral lungSee Treatment (NSCL-8)

See Treatment (NSCL-8)

Metastatic disease

Unresectable(pleural effusion) See Treatment (NSCL-10)

See Treatment for Metastasis(NSCL-11)

Unresectable(without effusion) See Treatment (NSCL-8)



Guidelines Index



INITIAL TREATMENT ADJUVANT TREATMENTMEDIASTINAL

BIOPSY FINDINGS

Negative for

M1 disease

Positive See Initial treatment ofM1 disease (NSCL-11)

No

progression

Progression

RT (if not given)i ± chemotherapyj�

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Brain MRI

PET/CT scan,

if not previously

done

d

Definitive concurrent

chemoradiation(category 1)or

i,k

iInduction

chemotherapy ± RTk

Surgery ± chemotherapy

(category 2B) ± RT

(if not given)

e

i

j

Thoracotomy

Resectable

UnresectableSee Treatmentaccording to pathologicstage (NSCL-1)

Surgical resection +

mediastinal lymph

node dissection or

lymph node sampling

e

See NSCL-3 NSCL-4OR

Margins

negative (R0)f

Margins positive

(R1, R2)fChemoradiation +

chemotherapy

i,k,l

N0–1

N2

Chemotherapy (category 1)+ RT

j

i

Definitive concurrent

chemoradiationi,k�

�

Brain MRI

PET/CT scan,

if not previously

done

d

Positive See Initial treatment of M1 disease (NSCL-11)

d

e

f

i

j

l

Positive PET/CT scan findings need pathologic or other radiologic confirmation. IfPET/CT scan positive in the mediastinum, lymph node status needs pathologicconfirmation.

.


.

.

For patients with negative margins, most NCCN institutions give sequentialchemotherapy/RT; for patients with positive margins, most NCCN institutions giveconcurrent chemo/RT ± chemotherapy.

k





NSCL-7

Negative for

M1 disease




Local

Systemic See Initial treatment ofM1 disease (NSCL-11)

T1-2,

T3 ( 7 cm),

N2 nodes

positive

�

T1-3, N0-1

(including

same lobe)

T3

(invasion),

N2 nodes

positive



Guidelines Index



INITIAL TREATMENT ADJUVANT TREATMENTCLINICAL PRESENTATION

RTi (if not given)

Surgerye

Surgerye

ChemotherapyjMargins negative

(R0)f

Concurrent chemoradiation

(category 1)

i,k

Induction

chemoradiation

Surgery

i,k

or

Induction

chemotherapy

or

j

e

e .f

i

j

l


.

.

For patients with negative margins, most NCCN institutions give sequentialchemotherapy/RT; for patients with positive margins, most NCCN institutions giveconcurrent chemo/RT ± chemotherapy.

The administration of chemotherapy in the adjuvant setting depends on the type ofneoadjuvant therapy and the patient’s tolerance.

k

s





NSCL-8

Chemotherapy (category 3)k

Margins negative

(R0)f

Margins positive

(R1, R2)f

Margins positive

(R1, R2)f

R1

R2Concurrent chemoradiationi,k

+ chemotherapy

Chemotherapyj

iin select patients

± RT (if not given)orObservation

s

Chemotherapyj



Chemoradiation + chemotherapyi,k,l

Stage IIIA (T4, N0-1)

Unresectable

(without effusion)

Margins negative

(R0)f

Margins positive

(R1, R2)f Concurrent chemoradiation (if tolerated)i,k,l

ChemotherapyjSeparate pulmonary

nodule(s), same lobe

or ipsilateral lung

Separate pulmonary

nodule(s),

contralateral lung

Treat as two primary lung

tumors if both curable

Stage IV, M1a:

Contralateral lung (solitary

nodule) or ipsilateral lung

(other lobe)

See Evaluation (NSCL-1)




Guidelines Index



d

i

Positive PET/CT scan findings need pathologic or other radiologic confirmation. If PET/CT scan positive in the mediastinum, lymph node status needs pathologicconfirmation.

.kSee Principles of Radiation Therapy (NSCL-C)



ASSESSMENT

INITIAL TREATMENT

Stage IIIB

(T1–3, N3)

�

�

�

�


PET/CT scan

Brain MRI

Pathologic confirmation of

N3 disease by either:MediastinoscopySupraclavicular lymph

node biopsyThoracoscopyNeedle biopsyMediastinotomyEndoscopic ultrasound

(EUS) biopsyEndobronchial ultrasound

(EBUS) biopsy

d

�

�

�

�

�

�

�

N3 negative See Initial treatment for stage I–IIIA (NSCL-1)

N3 positive

Concurrent

chemoradiation

(category 1)

i,k

Metastatic disease See Treatment for Metastasis (NSCL-11)

NSCL-9

Consolidation

chemotherapy

(category 2B)

k





Guidelines Index




ASSESSMENT

INITIAL TREATMENT

�

�

�

PET/CT scan

Brain MRI

Pathologic

confirmation of T4,

N2–3 disease by either:MediastinoscopySupraclavicular

lymph node biopsyThoracoscopyNeedle biopsyMediastinotomyEUS biopsyEBUS biopsy

d

�

�

�

�

�

�

�

Contralateral,

mediastinal

node positive

Contralateral,

mediastinal

node negative

Ipsilateral,

mediastinal

node negativeSee Treatment for Stage IIIA (NSCL-6)

Ipsilateral,

mediastinal

node positive

d

i

t

Positive PET/CT scan findings need pathologic or other radiologic confirmation. If PET/CT scan positive in the mediastinum, lymph node status needs pathologicconfirmation.

.

Most pleural effusions associated with lung cancer are due to tumor. There are few patients in whom multiple cytopathologic examinations of pleural fluid are negativefor tumor and fluid is non-bloody and not an exudate. When these elements and clinical judgment dictate the effusion is not related to the tumor, the effusion should beexcluded as a staging element. Pericardial effusion is classified using the same criteria.

kSee Principles of Radiation Therapy (NSCL-C)


Concurrent

chemoradiation

(category 1)

i,k

Metastatic disease See Treatment for Metastasis (NSCL-11)

See Treatment according toT, N, M stage NSCL-1

Negativet

Local therapy if necessary (eg, pleurodesis,

ambulatory small catheter drainage,

pericardial window) + treatment as for stage

IV disease (see NSCL-11)

Positivet

Thoracentesis or

pericardiocentesis ±

thoracoscopy if

thoracentesis indeterminate

NSCL-10

Concurrent

chemoradiation

(category 1)

i,k



Consolidation

chemotherapy

(category 2B)

k

Consolidation

chemotherapy

(category 2B)

kStage IIIB

(T4 extension,

N2–3)

Stage IV, M1a:

pleural or

pericardial

effusion



Guidelines Index




ASSESSMENT

INITIAL TREATMENT

Brainu

Resect brain lesion + whole

brain RT (WBRT) (category 1)

± stereotactic radiosurgery

(SRS) (category 2B)

or

SRS ± WBRT

Adrenal

Pathologic

diagnosis

by needle

or resection

Local therapy for adrenal

lesion (if lung lesion curable,

based on T and N stage)

(category 3)

or

See Systemic therapy

(NSCL-13)

�

�

�

�

Mediastinoscopy

Bronchoscopy

Brain MRI

PET/CT scand

d

u

Positive PET/CT scan findings need pathologic or other radiologic confirmation. If PET/CT scan positive in the mediastinum,lymph node status needs pathologic confirmation.

.

e .See Principles of Surgical Therapy (NSCL-B)

See NCCN CNS Guidelines

T1-2, N2; T3,

N1-2; Any T,

N3; T4, Any N

T1-2,

N0-1;

T3, N0

Surgical resection

of lung lesion

or

SRS (category 2B)

or

Chemotherapy

(category 2B)

e

Surgical

resection of

lung lesion

(category 2B)

e

Chemotherapy

(category 2B)

Workup as

clinically

indicated

See Systemic Therapy(NSCL-13)


NSCL-11

See Systemic Therapy(NSCL-13)



Stage IV,

M1b:

solitary

site

Stage IV, M1b:

disseminated



Guidelines Index



SURVEILLANCE THERAPY FOR RECURRENCE AND METASTASIS

See Systemictherapy andbest supportivecare (NSCL-13)

No evidence

of

disseminated

disease

Observation

or

Systemic

chemotherapy

(category 2B)

Evidence of

disseminated

disease

See Systemictherapy andbest supportivecare (NSCL-13)

Locoregional

recurrence

Distant

metastases

Endobronchial

obstruction

Resectable

recurrence

Superior vena cava

(SVC) obstruction

Severe hemoptysis

�

�

�

�

Laser/stent/other surgery

Brachytherapy

External-beam RT

Photodynamic therapy

�

�

Reresection

External-beam RT

�

�

External-beam RT

Stent

�

�

�

�

�

�

External-beam RT

Brachytherapy

Laser

Photodynamic therapy

Embolization

Surgery

Localized

symptoms

Diffuse brain

metastases

Bone metastasis

Solitary

metastasis

Palliative external-beam RT

Palliative external-beam RT

�

�

Palliative external-beam RT + orthopedic

stabilization, if risk of fracture

Consider bisphosphonate therapy

See pathway for Stage IV,M1b, solitary site (NSCL-11)

Disseminated

metastasesSee Systemic Therapy (NSCL-13)

NSCL-12

Mediastinal lymph

node recurrence

Concurrent chemoradiation

(if RT not previously given)



NED, stages I-IV:

History & physical and a

contrast-enhanced chest

CT every 4-6 mo for 2 y

(category 2B), then H&P

and a non-contrast-

enhanced chest CT

annually (category 2B)

Smoking cessation

counseling

PET or brain MRI is not

indicated for routine

follow-up

v

�

�

�

v .See Cancer Survivorship Care (NSCL-G)



Guidelines Index



Performance

status 0-1x

Performance

status 3-4

Erlotinib for EGFR mutation positive patientsorBest supportive care only ( )

gg

See NCCN Palliative Care Guidelines

Systemic therapy

and best

supportive care

w

w

x

y

aa

cc

.Performance status (PS) 2 patients have greater toxicity and potential for lower benefit than PS 0-1 patients.Any regimen with a high risk of thrombocytopenia and the potential risk of bleeding should be used with caution in combination with bevacizumab.Bevacizumab should be given until progression.Criteria for treatment with bevacizumab + chemotherapy: non-squamous NSCLC, and no history of hemoptysis. Bevacizumab should not be given as a single agent,

unless as maintenance if initially used with chemotherapy.Pemetrexed is not recommended for squamous histology.There is evidence of superior efficacy and reduced toxicity for cisplatin/pemetrexed in patients who do not have squamous histology, in comparison tocisplatin/gemcitabine. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage NSCLC. J Clin Oncol 2008;26:3543-3551.Pirker R, Periera JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open label randomised phase

III trial. Lancet 2009;373:1525-1531.Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57.

Full-dose cisplatin for PS 2 patients should be given selectively.Inoue A, Kobayashi K, Usui K, et al. First-line gefitinib for patients with advanced non-small cell lung cancer harboring epidermal growth factor receptor mutations

without indication for chemotherapy. J Clin Oncol 2009;27:1394-1400.

z

bb

dd

ee

ff

gg

See Systemic Therapy for Advanced or Metastatic Disease (NSCL-F)

THERAPY FOR RECURRENCE

AND METASTASIS

NSCL-13

Chemotherapy (category 1)orBevacizumab + chemotherapy (if criteria met)or

Cisplatin/pemetrexed (category 1) (if criteria met)

or

Cetuximab/vinorelbine/cisplatin

(category 2B)

or

Erlotinib for EGFR mutation positive patients

w

w,y,z

cc

dd

aa

bb

ee

FIRST-LINE THERAPY



Performance

status 2

Cetuximab/vinorelbine/cisplatin(category 2B)

orErlotinib for EGFR mutation positive patients

dd,ff

worChemotherapy

ee

See NSCL-14



Guidelines Index


Staging, Discussion, ReferencesNon-Small Cell Lung Cancer®

NCCNTHERAPY FOR RECURRENCE AND METASTASIS

Tumor response

hhevaluationif clinically indicated

Cycle 1

Continuation of current regimen until disease progression or

w Continuation maintenance bevacizumab (category 1)

or cetuximab (category 1) or bbpemetrexed (category 2B)

or w Switch maintenance

bbpemetrexed (category 2B) iior erlotinib (category 2B)

or docetaxel (category 3)or Observation

Progression

Tumor response or stable disease

Cycle 2

See Progressive Disease (NSCL-15)

Progression



NSCL-14



w .bbPemetrexed is not recommended for squamous histology.hhSome institutions advocate imaging (CT) studies to evaluate tumor progression after the first course.iiCappuzzo F, et al. Efficacy and safety of erlotinib as first-line maintenance in NSCLC following non-progression with chemotherapy: results from the phase III SATURN

Study. 13th World Conference on Lung Cancer 2009;Abstract A2.1


Tumor response evaluation

4-6 cycles (total)

Progression



Tumor response evaluation

Progressive Disease (NSCL-15)



Guidelines Index



Performance

status 0-2x

Performance

status 3-4

Performance

status 3-4

Best supportive

care

or

Clinical trial

(

)

See NCCN

Palliative Care

Guidelines

Performance

status 0-2x

PROGRESSIVE

DISEASE

w

x

jj

.

Performance status (PS) 2 patients have greater toxicity and potential for lower benefit than PS 0-1 patients.

Patients with a performance status of 3 were included in the National Cancer Institute of Canada-Clinical Trials Group (NCIC-CTG) trial BR.21.Erlotinib may be considered for PS 3 and 4 patients with EGFR mutation.


Performance

status 3, 4

Performance

status 0-2x

NSCL-15

Progression

ProgressionDocetaxel

or

Platinum doublet

(if erlotinib given

as first-line)

(category 2B)

w

w

w,jj

or

Pemetrexed

or

Erlotinib

Erlotinibw,jj

Best supportive care only

(

)

See NCCN Palliative Care

Guidelines

Best supportive care only

(

)

See NCCN Palliative Care

Guidelines

Best supportive

care only (

)

See

NCCN Palliative

Care Guidelines

SECOND-LINE THERAPY THIRD-LINE THERAPY





Guidelines Index



SURVEILLANCE

FINDINGS

DIAGNOSTIC EVALUATION THERAPY

Sputum cytology

positive (T0 disease);

chest CT negative

Second lung primary

on chest CT scanRefer to stage-specificevaluations (NSCL-1)

Treat according to staging findings

Rebronchoscope every 3 mo

Tis

Negative

�

�

�

�

Endobronchial ablation:

Laser

Surgical resection

Brachytherapy

Photodynamic therapyorRebronchoscope every 3 mo

T1–3 See NSCL-1

�

�

�

Bronchoscopy

Hematoporphyrin

fluorescence

Autofluorescence

NSCL-16





Guidelines Index



PRINCIPLES OF PATHOLOGIC REVIEW (1 of 2)

Pathologic Evaluation

Bronchioloalveolar carcinoma (BAC)

Immunohistochemical staining

�

�

�

�

�

�

�

�

�

�

The purpose of pathologic evaluation is to classify the lung cancer, determine the extent of invasion, establish the cancer involvement

status of the surgical margins, and determine the molecular abnormalities of lung cancer that may be able to predict for sensitivity and

resistance to epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKI).

The World Health Organization (WHO) tumor classification system provides the foundation for tumor diagnosis, patient therapy and

epidemiological and clinical studies.

The surgical pathology report should include the histologic classification published by the WHO for carcinomas of the lung.

BAC includes tumors where neoplastic cells spread along pre-existing alveolar structures (lepidic spread).

Pure BAC requires absence of invasion of stroma, pleura, or lymphatic spaces.

BAC is divided into three subtypes: mucinous, non-mucinous, and a mixed mucinous and nonmucinous or indeterminate form.

Nonmucinous BAC expresses the thyroid transcription factor-1 (TTF-1), CK7 and lacks CK20. Mucinous BAC may have an aberrant

immunophenotype, expressing CK20 and CK7, but reportedly lacking TTF-1 expression.

Immunostains are used to differentiate primary pulmonary adenocarcinoma from metastatic adenocarcinoma to the lung, to distinguish

adenocarcinoma from malignant mesothelioma and to determine the neuroendocrine status of tumors.

Differentiation between primary pulmonary adenocarcinoma and metastatic adenocarcinomaTTF-1 is a homeodomain-containing nuclear transcription protein of the Nkx2 gene family that is expressed in epithelial cells of the

embryonal and mature lung and thyroid.TTF-1 is important in distinguishing primary from metastatic adenocarcinoma: the majority of primary lung carcinomas is positive for

TTF-1 whereas metastatic adenocarcinoma to the lung is virtually always negative.Pulmonary adenocarcinoma of the lung is usually CK7+ and CK20- and therefore distinguishable from CK7- and CK20+ metastatic

adenocarcinoma of the colorectum.CDX-2 is a highly specific and sensitive marker for metastatic gastrointestinal malignancies, that could help distinguish from primary

lung tumors. Prostate specific antigen, prostatic acid phosphatase and gross cystic disease fluid protein 15 may identify metastatic

adenocarcinoma of prostate and breast origin, respectively.

Determining neuroendocrine status of tumorsChromogranin and synaptophysin are used to diagnose neuroendocrine tumors of the lung. All typical and atypical carcinoid tumors

stain with chromogranin and synaptophysin whereas small cell lung cancer is negative in 25% of cases.

Distinguishing between malignant mesothelioma and lung adenocarcinomaA panel of 4 markers, 2 positive in mesothelioma and 2 negative in mesothelioma (but positive in adenocarcinoma) is used routinely.The stains negative in mesothelioma, but positive in adenocarcinoma are CEA, B72.3, Ber-EP4 and MOC31.The stains sensitive and specific for mesothelioma are WT-1, calretinin, D2-40 and cytokeratin 5/6.

1

2,3

4

5

5

4

6

7,8

�

�

�

�

�

�

�

� Continued NSCL-A 2 of 2

NSCL-A1 of 2





Guidelines Index



PRINCIPLES OF PATHOLOGIC REVIEW (2 of 2)

NSCL-A2 of 2

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Fossella FV, Putnam JB & Komaki R. Lung Cancer. New York: Springer, 2003.

Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growthfactor receptor and in KRAS are predictive and prognostic indicators in patientswith non-small-cell lung cancer treated with chemotherapy alone and incombination with erlotinib.J Clin Oncol. 2005;23:5900-9.

Cappuzzo F, Ligorio C, Toschi L, et al. EGFR and HER2 gene copy number andresponse to first-line chemotherapy in patients with advanced non-small cell lungcancer (NSCLC). J Thorac Oncol 2007;2:423-9.

Brambilla E, Travis WD, Colby TV, et al. The new World Health Organizationclassification of lung tumours. Eur Respir J 2001;18:1059-68.

Travis WD, World Health Organization. International Agency for Research onCancer. International Academy of Pathology & International Association for theStudy of Lung Cancer. Pathology and genetics of tumours of the lung, pleura,thymus and heart. Lyon: IARC Press, 2004.

Goldstein NS & Thomas M. Mucinous and nonmucinous bronchioloalveolaradenocarcinomas have distinct staining patterns with thyroid transcription factorand cytokeratin 20 antibodies. Am J Clin Pathol 2001;116:319-25.

Chirieac LR, et al. Modern Pathology 2006;19:305A 1422.

Ordonez NG. D2-40 and podoplanin are highly specific and sensitiveimmunohistochemical markers of epithelioid malignant mesothelioma. Hum Pathol2005;36:372-80.

Cappuzzo F, Finocchiaro G, Metro G, et al. Clinical experience with gefitinib: anupdate. Crit Rev Oncol Hematol 2006;58:31-45.

Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlationwith clinical response to gefitinib therapy. Science 2004;304:1497-500.

Sequist LV, Joshi VA, Janne PA, et al. Response to treatment and survival ofpatients with non-small cell lung cancer undergoing somatic EGFR mutationtesting. Oncologist 2007;12:90-8.

Ji H, Li D, Chen L, et al. The impact of human EGFR kinase domain mutationson lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies.Cancer Cell 2006;9:485-95.

Shigematsu H, Gazdar AF. Somatic mutations of epidermal growth factorreceptor signaling pathway in lung cancers. Int J Cancer 2006;118:257-62.

Finberg KE, Sequist LV, Joshi VA, et al. Mucinous Differentiation Correlates withAbsence of EGFR Mutation and Presence of KRAS Mutation in LungAdenocarcinomas with Bronchioloalveolar Features. J Mol Diagn 2007;9:320-6.



Molecular Diagnostic Studies in Lung Cancer

�

�

�

�

EGFR is normally found on the surface of epithelial cells and is often overexpressed in a variety of human malignancies. Presence of

EGFR-activating mutations represents critical biological factors for proper patient selection.

There is a significant association between EGFR mutations, especially exon 19 deletion and exon 21 mutation, and response to TKIs.

EGFR and k-ras mutations are mutually exclusive in patients with lung cancer.

K-ras mutations are associated with intrinsic TKI resistance, and k-ras gene sequencing could be useful for the selection of patients as

candidates for TKI therapy.

9-12

13

14



Guidelines Index



� Determination of resectability should be performed by Board-certified thoracic surgeons who perform lung cancer surgery as a prominent

part of their practice.

Resection, including wedge resection, is preferred over ablation (radiofrequency ablation, cryotherapy, stereotactic radiation). Thoracic

surgical oncology consultation should be part of the evaluation of any patient being considered for curative local therapy.

Surgical staging and pulmonary resection should be performed by Board-certified thoracic surgeons who perform lung cancer surgery as

a prominent part of their practice.

The overall plan of treatment as well as needed imaging studies should be determined before any non-emergency treatment is initiated.

Thoracic surgeons should actively participate in multidisciplinary discussions and meetings regarding lung cancer patients (e.g.

multidisciplinary clinic and/or Tumor Board).

Anatomic pulmonary resection is preferred for the majority of patients with non-small cell lung cancer.

Sublobar resection - Segmentectomy and wedge resection should achieve parenchymal resection margins 2 cm or the size of the

nodule. Sublobar resection should also sample appropriate N1 and N2 lymph node stations unless not technically feasible without

substantially increasing the surgical risk. Segmentectomy (preferred) or wedge resection is appropriate in selected patients for the

following reasons:Poor pulmonary reserve or other major co-morbidity that contraindicates lobectomy

Peripheral nodule 2 cm with at least one of the following:Pure bronchioloalveolar carcinoma (BAC) histology (category 2B)

Nodule has 50% ground glass appearance on CT (category 2B)

Radiologic surveillance confirms a long doubling time ( 400 days) (category 2B)

Video-assisted thoracic surgery (VATS) is a reasonable and acceptable approach for patients with no anatomic or surgical

contraindications, as long as there is no compromise of standard oncologic and dissection principles of thoracic surgery.

Lung-sparing anatomic resection (sleeve lobectomy) preferred over pneumonectomy, if anatomically appropriate and margin-negative

resection achieved.

N1 and N2 node resection and mapping (ATS map) (minimum of three N2 stations sampled or complete lymph node dissection).

Formal ipsilateral mediastinal lymph node dissection is indicated for patients undergoing resection for stage IIIA (N2) disease.

Patients with pathologic stage II or greater should be referred to medical oncology for evaluation.

Consider referral to medical oncologist for stage IB, and consider referral to radiation oncologist for stage IIIA.

�

�

�

�

�

� � �

�

�

�

�

�

�

�

�

�

�

�

�

�

1

�

PRINCIPLES OF SURGICAL THERAPY

NSCL-B

1Peripheral is defined as lying in the outer one third of the lung parenchyma.





Guidelines Index



General Principles

�

�

�

�

�

�

�

Treatment recommendations should be made after joint consultation and/or discussion by a multidisciplinary team including surgical

oncologists, radiation oncologists, medical oncologists, pulmonologists, pathologists, and diagnostic radiologists.

Radiation therapy can be offered as an adjunct for operable patients with resectable diseases, as the primary local treatment for patients

with medically inoperable or unresectable diseases, and as an important palliative modality for patients with incurable diseases. The

terminology and abbreviations for radiation therapy are summarized in Table 1.

For resected tumors with pathologic mediastinal nodal involvement (pN2) and negative surgical margins, adjuvant chemotherapy followed

by postoperative radiotherapy is preferred, although the sequencing between radiation and chemotherapy in this setting has not been

established

For tumors with pN2 and positive resection margins, postoperative concurrent chemoradiotherapy is recommended if the patient is

medically fit. Radiation therapy should start earlier as local recurrence is the most common failure in this group of patients.

Conformal radiation therapy ± chemotherapy should be offered to patients with stage I, II, and III NSCLC who are medically inoperable but

of reasonable performance status and life expectancy. Modern technology can be applied as indicated. Both treatment outcome and cost

should be considered.

In patients receiving radiation therapy or chemoradiation with curative intent, treatment interruptions or dose reductions for manageable

acute toxicities (i.e. Grade 3 esophagitis or hematologic toxicities) should be minimized by conformal treatment planning and aggressive

supportive care.

Radiation therapy can be offered to primary or distant sites as palliative care for stage IV patients with extensive metastasis.

1-3

64,5

Commonly Used Radiation Therapy Abbreviations NSCL-C

5 of 7.

PRINCIPLES OF RADIATION THERAPY (1 of 7)

NSCL-C1 of 7



See Dose, Volume and Normal Tissue Constraints forConventionally Fractionated Radiation Therapy (NSCL-C 2 of 7)

See Radiation Simulation, Planning and Delivery (NSCL-C 3 of 7)

See Stereotactic Body Radiation Therapy (NSCL-C 4 of 7)

See Prophylactic Cranial Irradiation (NSCL-C 4 of 7)



Guidelines Index






NSCL-C2 of 7

Dose, Volume, and Normal Tissue Constraints for Conventionally Fractionated Radiation Therapy

�

�

�

� �

�

�

�

�

�

The dose recommendations for definitive and palliative radiation are summarized in Table 2.

. Tissue heterogeneity correction should be used in radiation treatment planning for all patients.

Preoperatively, a dose of 45-50 Gy in 1.8 to 2 Gy fraction size is recommended. Doses greater than 50 Gy in the preoperative setting have

been reported to be safe and achieved favorable survival outcome. However, this should only be performed with an experienced team.

Postoperative radiation dose should be based on margin status. Lung tolerance to radiation after surgery is remarkably smaller than those

with the presence of both lungs. Every effort should be made to minimize the dose of radiation therapy. More conservative consideration

should be applied for the dose constraints of normal lungs.

For definitive radiation therapy, the commonly prescribed dose is 60-70 Gy. Limited evidence suggested that a dose 74 Gy is

significantly associated with better survival in patients treated with radiation alone or sequential chemoradiation. Radiation dose may be

one significant factor for overall survival in stage I-II after radiation alone or stage III disease treated with concurrent chemoradiation.

When radiation is given concurrently with chemotherapy, a dose up to 74 Gy may be delivered safely, if the dose to normal structures are

strictly limited ( ). The role of high

dose radiation with concurrent chemotherapy is currently being tested in a phase III randomized trial (RTOG 0617).

For treatment volume consideration, PTV should be defined per ICRU-62 guidelines, based on GTV, plus CTV margin for microscopic

diseases, ITV margins for target motion, and margins for daily set-up errors. GTV should be confined to visible tumors (include both primary

and nodal diseases) on CT or PET-CT.

Regarding CTV of nodal regions, elective nodal irradiation (ENI) remains controversial and should be individualized based on tumor volume,

dosimetric parameters of adjacent normal structures, and comorbid conditions. Involved field radiation to high dose without ENI has been

shown to allow higher dose radiation with acceptable toxicity and low risk of isolated nodal relapse.

In patients who receive postoperative radiotherapy, CTV should consist of the bronchial stump and high-risk draining lymph node stations.

It is essential to evaluate the dose volume histogram (DVH) of critical structures and to limit the doses to the lungs, heart, esophagus, brachial

plexus, and spinal cord (See T ) to

minimize normal tissue toxicity. These limits are largely empirical.

For patients receiving postoperative radiation therapy, more strict DVH parameters should be considered for the lung. The exact limit is

unknown for lobectomy cases; mean lung dose should be limited to less than 8.5 Gy in pneumonectomy patients.

7

8-10

2,4

11,12

13

14 15

16-18

19

11,13,20-23

24

25-32

See Table 3.

able 3.

Recommended Doses for Conventionally

Fractionated Radiation Therapy NSCL-C 5 of 7

Normal Tissue Dose Volume Constraints for Conventionally Fractionated 3DCRT NSCL-C 5 of 7

Normal Tissue Dose Volume Constraints for Conventionally Fractionated 3DCRT NSCL-C 5 of 7



See Radiation Simulation, Planning and Delivery (NSCL-C 3 of 7)



Guidelines Index




NSCL-C3 of 7

Radiation Simulation, Planning and Delivery

�

�

�

�

�

Treatment planning should be performed by CT scans obtained in the treatment position. IV contrast should be used for better target

delineation whenever possible, especially in patients with central tumors or with nodal disease. PET-CT is preferable in cases with

significant atelectasis and when IV contrast is contraindicated. PET-CT can significantly improve the target accuracy.

In patients who receive induction chemotherapy, attempts should be made to obtain a baseline planning CT prior to induction

chemotherapy. If feasible, the initial radiation fields should cover the pre-chemotherapy tumor volume, and the cone-down fields should

cover the post-chemotherapy tumor volume. However, in patients with compromised lung function or large initial tumor volume, the

post-chemotherapy volume can be used to avoid excessive pulmonary toxicity.

Photon beam energy should be individualized based on the anatomic location of the tumors and beam angles. In general, photon beam

energy between 4 to 10 MV is recommended for beams passing through low density lung tissue before entering the tumor. For large

mediastinal tumors or tumors attached to chest wall, 15 MV or 18 MV energies can be considered for more optimal dose arrangement.

In certain situations where there is a large volume of normal lung being irradiated or where tumors are located close to critical

structures (i.e. spinal cord), intensity modulated radiotherapy (IMRT) may be considered for high-dose radiation to avoid overdose to

normal tissues. Significantly lower risk of radiation pneumonitis and improved overall survival have been observed with IMRT compared

to 3-D conformal radiation therapy for lung cancer. When IMRT is used, the NCI IMRT guideline

( ) should be followed. Under strictly defined protocols, proton

therapy may be allowed. When IMRT and proton therapy are used, daily image guidance at delivery should be used for quality

assurance. The modality of IGRT should be based on the institutional experience and the treatment accuracy.

Whenever feasible, respiratory motion should be managed. Acceptable methods of accounting for tumor motion, per

guideline, include: 1) Motion-encompassing methods such as slow CT scanning, inhale and exhale breath-hold CT, four-dimensional

(4-D) respiration-correlated CT, 2) Respiratory gating methods using an external respiration signal or using internal fiducial markers, 3)

Breath-hold methods by deep-inspiration breath-hold, active-breathing control (ABC) device, self breath-hold without respiratory

monitoring, 4) Forced shallow breathing with abdominal compression, and 5) Real-time tumor-tracking methods.

33

34

35-39

AAPM Task Group

76

http://www.rtog.org/pdf_document/NCI_IMRT_Guidelines_2006.pdf







Guidelines Index



Stereotactic Body Radiation Therapy (SBRT)

Prophylactic Cranial Irradiation (PCI)

�

�

�

�

�

SBRT provides statistically significantly higher 5-year survival than 3DCRT in stage I NSCLC. SBRT can be considered for inoperable

stage I patients with node negative peripheral lesions (See ) that are

less than 5 cm in maximal dimension or limited lung metastasis.

SBRT fractionation regimens range from one single fraction to 3 fractions, 4 fractions, and 5 fractions (See

). While the optimal number of fractionation may be estimated based on the tumor size and total

dose, an accumulative BED of 100 Gy is associated with better survival. RTOG 0915 is ongoing to compare the outcomes between

one single fraction and 4 fractions.

SBRT Normal tissue dose constraints should be strictly followed (See

).

The role of prophylactic brain irradiation is controversial. The recommendation of whole brain irradiation should be a decision after

multidisciplinary discussion, weighing the potential benefit over the risk for each individual patient. Dose and fractionation of PCI can

be the same as for small cell lung cancer (25 Gy in 10 fractions over 2 weeks).

40

41,42 43

44 45,46 47 48,49

50 51

52

Figure 1.

Table 4.

Table 5.

Schema of Central and Peripheral Locations NSCL-C 6 of 7

SBRT

Regimens and Indications NSCL-C 6 of 7

Normal Tissue Dose Volume Constraints for SBRT NSCL-

C 6 of 7


NSCL-C4 of 7





Guidelines Index



3DCRT 3-D Conformal Radiation

Therapy

GTV Gross Tumor Volume

CTV Clinical Target Volume

PTV Planning Target Volume

ITV Internal Target Volume

BED Biological Equivalent Dose

OAR Organ At Risk

V20 % Volume an OAR

Receiving 20 Gy�

MLD Mean Lung Dose

ABC Active Breathing Control

IMRT Intensity Modulated

Radiation Therapy

OBI On Board Image

IGRT Image Guided Radiation

Therapy

SBRT Stereotactic Body Radiation

Therapy

4DCT 4 Dimensional Computerized

Tomography

CBCT Cone Beam Computerized

Tomography




Table 1. Commonly Used Radiation Therapy

Abbreviations

Table 2. Recommended Doses for Conventionally Fractionated Radiation Therapy

Treatment Type Total Dose Fraction

Size

Preoperative 45-50 Gy 1.8-2 Gy

Postoperative

� Negative margins

�

�

Extracapsular nodal extension or microscopic

positive margins

Gross residual tumors

Definitive

�

�

Radiation alone or sequential chemoradiation

Concurrent chemotherapy

4-5 weeks

Palliative

�

�

�

�

Obstructive disease (SVC syndrome or

obstructive pneumonia)

Bone metastases with soft tissue mass

Bone metastases without soft tissue mass

Brain metastasis

Treatment

Duration

50 Gy

54-60 Gy

60 to 70 Gy

1.8-2 Gy

1.8-2 Gy

1.8-2 Gy

4-5 weeks

5-6 weeks

6-7 weeks

60-74 Gy

60 to 70 Gy2 Gy

2 Gy

6-7.5 weeks

6-7 weeks

30-45 Gy

30 Gy

8 Gy

See CNS

Guidelines

3 Gy

3 Gy

8 Gy

See CNS

Guidelines

2-3 weeks

2 weeks

1 day

See CNS

Guidelines

NSCL-C5 of 7

Table 3. Normal Tissue Dose Volume Constraints for Conventionally Fractionated 3DCRT*

Structures

Spinal Cord

Lung

Heart

Esophagus

Limits

50 Gy in 1.8-2 Gy fractions

V20 < 37%

MLD < 20 Gy

V40 < 100%

V45 < 67%

V60 < 33%

Mean dose < 34 Gy

Brachial Plexus 66 Gy in 1.8-2 Gy fractions

*The limits are consistent with those of the ongoing

phase III trial RTOG 0617.

Vxx refers to the percentage of whole organ

receiving more or equal to xx Gy.

Lung V20 refers to the percentage of both lungs

with subtraction of overlapping CTV receiving 20

Gy, MLD=mean total lung dose.

�



Guidelines Index






NSCL-C6 of 7

Regimen

30-34 Gy x 1

15-20 Gy x 3

12-12.5 Gy x 4

10-11 Gy x 5

Indications

Peripheral small (< 2 cm) tumors, > 1 cm from chest wall

Peripheral < 5 cm tumors, > 1 cm from chest wall

Peripheral tumors, particularly those < 1 cm from chest wall

Peripheral tumors, particularly those < 1 cm from chest wall

Table 4. SBRT Regimens and Indications for Lung Tumors

Table 5. Normal Tissue Dose Volume Constraints for SBRT*

Spinal

cord

Esophagus

Brachial

plexus

Heart/

pericardium

Great

vessels

14 Gy

15.4 Gy

17.5 Gy

22 Gy

37 Gy

18 Gy

(6 Gy/fx)

30 Gy

(10 Gy/fx)

21 Gy

(7 Gy/fx)

30 Gy

(10 Gy/fx)

39 Gy

13 Gy/fx

26 Gy

(6.5 Gy/fx)

30 Gy

(7.5 Gy/fx)

27.2 Gy

(6.8 Gy/fx)

34 Gy

(8.5 Gy/fx)

49 Gy

12.25 Gy/fx

30 Gy

(6 Gy/fx)

32.5 Gy

(6.5 Gy/fx)

30 Gy

(6 Gy/fx)

35 Gy

(7 Gy/fx)

55 Gy

11 Gy/fx

OAR 1 Fraction 3 Fractions 4 Fractions 5 Fractions

Rib

Skin

Stomach

Figure 1. Schema of Central and Peripheral Locations

Peripheral tumors are those located 2 cm in all

directions around the proximal bronchial tree.

�

Defines zone of the

proximal bronchial treeTrachea/

Large Bronchus

20.2 Gy 30 Gy

(10 Gy/fx)

34.8 Gy

(8.7 Gy/fx)

40 Gy

(8 Gy/fx)

30 Gy 30 Gy

(10 Gy/fx)

32 Gy

(7.8 Gy/fx)

32.5 Gy

(6.5 Gy/fx)

26 Gy 30 Gy

10 Gy/fx

36 Gy

(9 Gy/fx)

40 Gy

8 Gy/fx

12.4 Gy 27 Gy

9 Gy/fx30 Gy

(7.5 Gy/fx)

35 Gy

7 Gy/fx

*The limits are the maximum point doses, based on a combined consideration ofrecommendations from ongoing multicenter trials (RTOG 0618 and RTOG 0915).

Reprinted with permission 2008 American Society ofClinical Oncology. All rights reserved. Timmerman R, et al.J Clin Oncol 24, 2006:4833-4839.

©



Guidelines Index



1

2

3

4

5

6

33

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35

36

37

38

39

40

41

42

43

44

45

46

47

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49

50

51

52

The Lung Cancer Study Group. Effects of postoperative mediastinal radiationtherapy on completely resected stage II and stage III epidermoid cancer ofthe lung. N Engl J Med 1986;315:1377-1381.

Keller SM, Adak S, Wagner H, et al. A randomized trial of postoperativeadjuvant therapy in patients with completely resected stage II or IIIA non-small cell lung cancer. Eastern Cooperative Oncology Group. N Engl J Med.2000;343:1217-1222.

Douillard JY, Rosell R, De Lena M, et al. Impact of postoperative radiationtherapy on survival in patients with complete resection and stage I, II, andIIIA non-small cell lung cancer treated with adjuvant therapy: the adjuvantNavelbine International Trialist Association (ANITA) Randomized Trial. Int JRadiat Oncol Biol Phys 2008;72:695-701.

Bradley JD, Paulus R, Graham MV, et al. Phase II trial of postoperativeadjuvant paclitaxel/carboplatin and thoracic radiotherapy in resected stage IIand IIIA non-small cell lung cancer: promising long term results of theRadiation Therapy Oncology Group--RTOG 9705. J Clin Oncol2005;23:3480-3487.

Feigenberg SJ, Hanlon AL, Langer C, et al. A phase II study of concurrentcarboplatin and paclitaxel and thoracic radiotherapy for completely resectedstage II and IIIA non-small cell lung cancer. J Thorac Oncol 2007;2:287-292.

Jaklitsch MT, Herndon JE 2nd, DeCamp MM Jr, et al. Nodal downstagingpredicts survival following induction chemotherapy for stage IIIA (N2) non-small cell lung cancerin CALGB protocol #8935. J Surg Oncol 2006;94:599-606.

MacManus M, Nestle U, Rosenzweig KE, et al.Radiother

Oncol 2009;91:85-94.Liao ZX, Komaki RR, Thames HD Jr, et al. Influence of technologicadvances on outcomes in patients With unresectable, locally advancednon-small-cell lung cancer receiving concomitant chemoradiotherapy. IntJ Radiat Oncol Biol Phys 2009 Jun 8. [Epub ahead of print]Chang JY, Zhang X, Wang X, et al. Significant reduction of normal tissuedose by proton radiotherapy compared with three-dimensional conformalor intensity-modulated radiation therapy in stage I or stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2006;65:1087-96.

Cox JD, Sejpal S, Komaki R, et al. Proton therapy with concurrentchemotherapy can reduce toxicity and allow higher radiation doses inadvanced non-small cell lung cancer. J Thorac Oncol 2008;3:S303-S304.Komaki R, et al. Rad Oncol 2009;90(suppl 4):61.Bush DA, Slater JD, Shin BB, et al. Hypofractionated proton beamradiotherapy for stage I lung cancer. Chest 2004;126:1198-1203Nihei K, Ogino T, Ishikura S, Nishimura H. High-dose proton beam therapyfor stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys2006;65:107-111.Gruters JP, Kessels AG, Pijls-Johannesma M, et al. Comparison of theeffectiveness of radiotherapy with photons, protons, and carbon-ions fornon-small cell lung cancer: A meta-analysis. Radiother Oncol 2009;Sept 3[Epub ahead of print]Onishi H, Araki T, Shirato H, et al. Stereotactic hypofractionated high-doseirradiation for stage I nonsmall cell lung carcinoma: clinical outcomes in245 subjects in a Japanese multiinstitutional study. Cancer2004;101:1623-31.Timmerman R, McGarry R, Tiannoutsos C, et al. Excessive toxicity whentreating central tumors in a phase II study of stereotactic body radiationtherapy for medically inoperable early-stage lung cancer. J Clin Oncol2006;24:4833-9.Guckenberger M, Wulf J, Mueller G, et al. Dose response relationship forimage-guided stereotactic body radiotherapy of pulmonarytumors:relevance of 4D dose calculation. Int J Radiat Oncol Biol Phys2009;74:47-54.Hara R, Itami J, Kondo T, et al. Clinical outcomes of single-fractionstereotactic radiation therapy of lung tumors. Cancer 2006;106:1347-52.Baumann P, Nyman J, Hoyer M, et al. Outcome in a prospective phase IItrial of medically inoperable stage I non-small-cell lung cancer patientstreated with stereotactic body radiotherapy. J Clin Oncol 2009;27:3290-6.Fakiris AJ, McGarry RC, Yiannoutsos CT, et al. Stereotactic body radiationtherapy for early-stage non-small-cell lung carcinoma: four year results ofa prospective phase II study. Int J Radiat Oncol Biol Phys 2009;75:677-82.Chang JY, Balter PA, Dong L, et al. Stereotactic body radiation therapy incentrally and superiorly located stage I or isolated recurrent non-small-celllung cancer. Int J Radiat Oncol Biol Phys 2008;72:967-71.Takeda A, Sanuki N, Kunieda E, et al. Stereotactic body radiotherapy forprimary lung cancer at a dose of 50 Gy total in five fractions to theperiphery of the planning target volume calculated using a superpositionalgorithm. Int J Radiat Oncol Biol Phys 2009;73:442-8.Stephans KL, Djemil T, Reddy CA, et al. A comparison of two stereotacticbody radiation fractionation schedules for medically inoperable stage Inon-small cell lung cancer: the Cleveland Clinic experience. J ThoracOncol 2009;4:976-82.Jin JY, Kong FM, Chetty IJ, et al. Impact of fraction size on lung radiationtoxicity: hypofractionation may be beneficial in dose escalation ofradiotherapy for lung cancers. Int J Radiat Oncol Biol Phys 2009;Jul 3.[Epub ahead of print]Onishi H, Shirato H, Nagata Y, et al. Hypofractionated stereotacticradiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updatedresults of 257 patients in a Japanese multi-institutional study. J ThoracOncol 2007;2(7 suppl 3):S94-100.Le Pechoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stagesmall-cell lung cancer in complete remission after chemotherapy andthoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, andIFCT 99-01): a randomised clinical trial. Lancet Oncol 2009;10:467-74.

7

8

9

10

11

12

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgicalresection for superior sulcus non-small-cell lung carcinomas: long-termresults of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). JClin Oncol 2007;25:313-8.

Cerfolio RJ, Bryant AS, Jones VL, Cerfolio RM. Pulmonary resection afterconcurrent chemotherapy and high dose (60Gy) radiation for non-small celllung cancer is safe and may provide increased survival. Eur J CardiothoracSurg 2009 Apr;35(4):718-23; discussion 723.

Kwong KF, Edelman MJ, Suntharalingam M, et al. High-dose radiotherapy intrimodality treatment of Pancoast tumors results in high pathologic completeresponse rates and excellent long-term survival. J Thorac Cardiovasc Surg2005;129:1250-7.Sonett JR, Suntharalingam M, Edelman MJ, et al. Pulmonary resection aftercurative intent radiotherapy (>59 Gy) and concurrent chemotherapy in non-small-cell lung cancer. Ann Thorac Surg 2004;78:1200-5.Bradley J, Graham MV, Winter K, et al. Toxicity and outcome results ofRTOG 9311: a phase I-II dose-escalation study using three-dimensionalconformal radiotherapy in patients with inoperable non-small-cell lungcarcinoma. Int J Radiat Oncol Biol Phys 2005;61:318-28Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment ofbrain metastases: a randomized controlled trial. JAMA 2006;295:2483-91.Kong FM, Ten Haken RK, Schipper MJ, et al. High-dose radiation improvedlocal tumor control and overall survival in patients withinoperable/unresectable non-small-cell lung cancer: long-term results of aradiation dose escalation study. Int J Radiat Oncol Biol Phys 2005;63:324-33.Zhao L, West BT, Hayman JA, et al. High radiation dose may reduce thenegative effect of large gross tumor volume in patients with medicallyinoperable early-stage non-small cell lung cancer. Int J Radiat Oncol BiolPhys 2007;68:103-10.Wang L, Correa CR, Zhao L, et al. The effect of radiation dose andchemotherapy on overall survival in 237 patients with Stage III non-small-celllung cancer. Int J Radiat Oncol Biol Phys 2009;73:1383-90.Socinski MA, Rosenman JG, Halle J, et al. Dose-escalating conformalthoracic radiation therapy with induction and concurrent carboplatin/paclitaxelin unresectable stage IIIA/B nonsmall cell lung carcinoma: a modified phaseI/II trial. Cancer 2001;92:1213-23.Schild SE, McGinnis WL, Graham D, et al. Results of a Phase I trial ofconcurrent chemotherapy and escalating doses of radiation for unresectablenon-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2006;65:1106-11.

Bradley JS, Graham M, Suzanne S, et al. Phase I Results of RTOG L-0117; a Phase I/II Dose Intensification Study Using 3DCRT andConcurrent Chemotherapy for Patients with Inoperable NSCLC. J ClinOncol 2005 ASCO Annual Meeting Proceedings;23(abstract 7063)Belderbos JS, Kepka L, Kong FM, et al. Report from the InternationalAtomic Energy Agency (IAEA) consultants' meeting on elective nodalirradiation in lung cancer: non-small-Cell lung cancer (NSCLC). Int JRadiat Oncol Biol Phys 2008;72:335-42.Yuan S, Sun X, Li M, et al. A randomized study of involved-fieldirradiation versus elective nodal irradiation in combination with concurrentchemotherapy for inoperable stage III nonsmall cell lung cancer. Am JClin Oncol 2007;30:239-44.Rosenzweig KE, Sura S, Jackson A, Yorke E. Involved-field radiationtherapy for inoperable non small-cell lung cancer. J Clin Oncol2007;25:5557-61.Sanuki-Fujimoto N, Sumi M, Ito Y, et al. Relation between elective nodalfailure and irradiated volume in non-small-cell lung cancer (NSCLC)treated with radiotherapy using conventional fields and doses. RadiotherOncol 2009;91:433-7.Sulman EP, Komaki R, Klopp AH, et al. Exclusion of elective nodalirradiation is associated with minimal elective nodal failure in non-smallcell lung cancer. Radiat Oncol 2009;4:5.Kelsey CR, Light KL, Marks LB. Patterns of failure after resection of non-small-cell lung cancer: implications for postoperative radiation therapyvolumes. Int J Radiat Oncol Biol Phys 2006;65:1097-105.Kong FM, Pan C, Eisbruch A, Ten Haken RK. Physical models andsimpler dosimetric descriptors of radiation late toxicity. Semin RadiatOncol. 2007;17:108-20.Graham MV, Purdy JA, Emami B, et al. Clinical dose-volume histogramanalysis for pneumonitis after 3D treatment for non-small cell lung cancer(NSCLC). Int J Radiat Oncol Biol Phys 1999;45:323-9.Kong FM, Hayman JA, Griffith KA, et al. Final toxicity results of aradiation-dose escalation study in patients with non-small-cell lungcancer (NSCLC): predictors for radiation pneumonitis and fibrosis. Int JRadiat Oncol Biol Phys 2006;65:1075-86.Hernando ML, Marks LB, Bentel GC, et al. Radiation-induced pulmonarytoxicity: a dose-volume histogram analysis in 201 patients with lungcancer. Int J Radiat Oncol Biol Phys 2001;51:650-9.Kim TH, Cho KH, Pyo HR, et al. Dose-volumetric parameters forpredicting severe radiation pneumonitis after three-dimensionalconformal radiation therapy for lung cancer. Radiology 2005;235:208-15.Wang S, Liao Z, Wei X, et al. Analysis of clinical and dosimetric factorsassociated with treatment-related pneumonitis (TRP) in patients withnon-small-cell lung cancer (NSCLC) treated with concurrentchemotherapy and three-dimensional conformal radiotherapy (3D-CRT).Int J Radiat Oncol Biol Phys 2006;66:1399-407.Rose J, Rodrigues G, Yaremko B, et al. Systematic review of dose-volume parameters in the prediction of esophagitis in thoracicradiotherapy. Radiother Oncol 2009;91:282-7.Hall WH, Guiou M, Lee NY, et al. Development and validation of astandardized method for contouring the brachial plexus: preliminarydosimetric analysis among patients treated with IMRT for head-and-neckcancer. Int J Radiat Oncol Biol Phys 2008;72:1362-7.

Use of PET and PET/CTfor radiation therapy planning: IAEA expert report 2006-2007.

13

PRINCIPLES OF RADIATION THERAPY - References (7 of 7)

NSCL-C7 of 7



Guidelines Index



CHEMOTHERAPY REGIMENS FOR ADJUVANT THERAPY

NSCL-D

Cisplatin 50 mg/m days 1 and 8

Vinorelbine 25 mg/m days 1, 8, 15, 22

2

2

Cisplatin 100 mg/m on day 1

Vinorelbine 30 mg/m days 1, 8, 15, 22

2

2

Every 28 days for 4 cyclesa

Every 28 days for 4 cyclesb,c

Published Chemotherapy Regimens Schedule




Etoposide 100 mg/m days 1-3

2

2Every 28 days for 4 cyclesb

See Chemoradiation onpage NSCL-E

Cisplatin 80 mg/m on day 1, 22, 43, 64

Vinblastine 4 mg/m days 1, 8, 15, 22then every 2 wks after day 43

2

2Every 21 days for 4 cyclesb

Cisplatin 75-80 mg/m day 1;

Vinorelbine 25-30 mg/m days 1 + 8

2

2Every 21 days for 4 cyclesa

Chemotherapy Regimens for patients with comorbidities

or patients not able to tolerate cisplatin

Paclitaxel 200 mg/m on day 1Carboplatin AUC 6 on day 1

2 Every 21 daysd

Schedule

Other Acceptable Cisplatin-

based Regimens


Gemcitabine 1250 mg/m on days 1, 8

2

2

Cisplatin 75 mg/m

Docetaxel 75 mg/m

2

2

Every 21 days

Every 21 days e

Schedule

aWinton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-lung cancer. N Engl J Med 2005;352:2589-2597.b

c

d

e

Arriagada R, Bergman B, Dunant A, et al. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients withcompletely resected non-small cell lung cancer. N Engl J Med 2004;350:351-60.

Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lungcancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006;7(9):719-727.

Strauss GM, Herndon III JE, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small cell lung cancer: CALGB 9633with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008;26:5043-5051.

Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin foradvanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003;21(16):3016-24. Epub 2003 Jul 1.

Pemetrexed 500 mg/m on day 1

Cisplatin 75 mg/m on day 1for adenocarcinoma and large cell

carcinoma and NSCLC NOS

(without specific histologic subtype)

2

2Every 21 days for 4

cycles



Guidelines Index



Cisplatin 100 mg/m day 1, 29

Vinblastine 5 mg/m /weekly x 5Concurrent thoracic RT 60 Gy (preferred)

2

2

b

Concurrent Chemotherapy/RT Regimens*

Paclitaxel 45-50 mg/m weekly over 1 hour

Carboplatin AUC = 2 mg/mL/min over 30 min weeklyConcurrent thoracic RT 63 Gy/7 wks/34 fractions (category 2B)

2

c

Cisplatin 50 mg/m on day 1, 8, 29, and 36

Etoposide 50 mg/m days 1-5, 29-33Concurrent thoracic RT (total dose, 61 Gy) (preferred)

2

2

a

CHEMOTHERAPY REGIMENS USED WITH RADIATION THERAPY

NSCL-E



a

b

c

d

Albain KS, Crowley JJ, Turrisi AT III, et al. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: A SouthwestOncology Group Phase II Study, SWOG 9019. J Clin Oncol 2002;20:3454-3460.

Curran WJ, Scott CB, Langer CJ, et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemoradiation for patients with unresectedstage III NSCLC: RTOG 9410. Proc Am Soc Clin Oncol 2003;22:621 (abstr 2499).

Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomizedphase II locally advanced multi-modality protocol. J Clin Oncol 2005;23(25):5883-5891.

Gandara DR, Chansky K, Albain KS, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II SouthwestOncology Group Study S9504. J Clin Oncol 2003;21(10):2004-2010.

Sequential Chemotherapy/RT Regimens

Paclitaxel 200 mg/m every 3 weeks over 3 hours, 2 cycles

Carboplatin AUC 6, 2 cyclesfollowed by thoracic RT 63 Gy beginning on day 42

2

c

Cisplatin 100 mg/m on day 1, 29

Vinblastine 5 mg/m /weekly on days 1, 8, 15, 22, 29followed by RT with 60 Gy in 30 fractions beginning on day 50

2

2

b

Concurrent Chemotherapy/RT Followed by Chemotherapy

Paclitaxel 45-50 mg/m weekly

Carboplatin AUC 2, concurrent thoracic RT 63 Gyfollowed by 2 cycles of paclitaxel 200 mg/m and carboplatin AUC 6 (category 2B)

2

2 c

Cisplatin 50 mg/m on day 1, 8, 29, 36

Etoposide 50 mg/m days 1-5, 29-33Concurrent thoracic RT (total dose, 61 Gy)followed by cisplatin 50 mg/m and etoposide 50 mg/m x 2 additional cycles (category 2B) or followed by

docetaxel started 4-6 wks after chemoradiation at an initial dose of 75 mg/m x 3 doses every 3 weeks (category 3)

2

2

d

2 2 a

2

*Randomized data support full-dose cisplatin over carboplatin-based regimens. Carboplatin regimens have not been adequately tested.



Guidelines Index



NSCL-F1 of 3

ADVANCED DISEASE:

Baseline prognostic variables (stage, weight loss, PS, gender) predict survival.

Platinum-based chemotherapy prolongs survival, improves symptom control and yields superior quality of life compared to best supportive

care.

Histology of NSCLC is important in the selection of systemic therapy.

New agent platinum combinations have generated a plateau in overall response rate ( 25-35%), time to progression (4-6 mo), median

survival (8-10 mo), 1 y survival rate (30-40%) and 2 y survival rate (10-15%) in fit patients.

No specific platinum-based cytotoxic combination is clearly superior.

Unfit of any age (performance status 3-4) do not benefit from cytotoxic treatment, except erlotinib for EGFR mutation positive patients.

Bevacizumab + chemotherapy or chemotherapy alone is indicated in PS 0-1 patients with advanced or recurrent NSCLC. Bevacizumab

should be given until disease progression.

Cetuximab +

Two drug regimens are preferred; a third cytotoxic drug does not increase survival, with the exception of bevacizumab or cetuximab in

treatment-naïve PS 0-1 NSCLC.

Single agent therapy or platinum-based combinations are a reasonable alternative in PS 2 patients or the elderly.

Systemic chemotherapy is not indicated in PS 3 or 4 patients.

In locally advanced NSCLC, chemoradiation is superior to radiation alone: concurrent chemoradiation appears to be better than sequential

chemoradiation.

Cisplatin-based combinations have been proven superior to best supportive care in advanced, incurable disease, with improvement in

median survival of 6-12 wks, and a doubling of one-year survival rates (absolute 10-15% improvement).

Cisplatin or carboplatin have been proven effective in combination with any of the following agents: paclitaxel, docetaxel, gemcitabine,

vinorelbine, irinotecan, etoposide, vinblastine, pemetrexed.

New agent/non-platinum combinations are reasonable alternatives if available data show activity and tolerable toxicity (eg,

gemcitabine/docetaxel).If patient has a known KRAS mutation, therapy other than erlotinib should be considered first.

�

�

�

� �

�

�

�

�

�

�

�

�

�

�

�

�

�

First-line therapy

vinorelbine/cisplatin is indicated in PS 0-2 patients with advanced or recurrent NSCLC.

Erlotinib is indicated for EGFR mutation positive patients.

There is evidence of superior efficacy and reduced toxicity for cisplatin/pemetrexed in patients with nonsquamous histology, in comparison

to cisplatin/gemcitabine.

�

See Maintenance Chemotherapy, Second- and Third-line therapy NSCL-F (2 of 3)

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE (1 OF 3)





Guidelines Index



NSCL-F2 of 3




Maintenance Therapy

Continuation maintenance refers to the use of at least one of the agents given in first line, beyond 4-6 cycles, in the absence of disease

progression. Switch maintenance refers to the initiation of a different agent, not included as part of the first-line regimen, in the absence

of disease progression, after 4-6 cycles of initial therapy.

�

�

Continuation Maintenance: Biologic agents given in combination with conventional chemotherapy should be continued until evidence

of disease progression or unacceptable toxicity, as per the design of the clinical trials that led to their approval. There are no

randomized data supporting the continuation maintenance of conventional cytotoxic agents beyond 4-6 cycles of therapy.Continuation of bevacizumab after 4-6 cycles of platinum-doublet chemotherapy and bevacizumab (category 1).Continuation of cetuximab after 4-6 cycles of cisplatin, vinorelbine, and cetuximab (category 1).Continuation of pemetrexed after 4-6 cycles of cisplatin and pemetrexed chemotherapy, for patients with histologies other than

squamous cell carcinoma (category 2B).

Switch Maintenance: Two recent studies have shown a benefit in progression-free and overall survival with the initiation of pemetrexed

or erlotinib after first-line chemotherapy, in patients without disease progression after 4-6 cycles of therapy.Initiation of pemetrexed after 4-6 cycles of first-line platinum-doublet chemotherapy, for patients with histologies other than

squamous cell carcinoma (category 2B).Initiation of erlotinib after 4-6 cycles of first-line platinum-doublet chemotherapy (category 2B).Initiation of docetaxel after 4-6 cycles of first-line platinum-doublet chemotherapy (category 3).Close follow-up of patients without therapy is a reasonable alternative to switch maintenance.

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Second-line therapy

Third-line therapy

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In patients who have experienced disease progression either during or after first-line therapy, single-agent docetaxel, pemetrexed, or

erlotinib are established second-line agents.Docetaxel has been proven superior to BSC, vinorelbine, or ifosfamide with improved survival/QOL.Pemetrexed has been shown to be superior to docetaxel with less toxicity in patients with adenocarcinoma and large cell carcinoma.Erlotinib has proven superior to BSC with significantly improved survival and delayed time to symptom deterioration.

Erlotinib has proven statistically superior to BSC with respect to survival.

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See Specific Systemic Agents on page NSCL-F (3 of 3)



Guidelines Index



NSCL-F3 of 3

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Cisplatin

Carboplatin

Paclitaxel

Docetaxel

Vinorelbine

Gemcitabine

Etoposide

Irinotecan

Vinblastine

Mitomycin

Ifosfamide

Pemetrexed

Erlotinib

Bevacizumab

Albumin-bound paclitaxel

1-9

4,6-11

1,4,6,8-11

5,7,8,12,13

6-8

3,5,6,8,9,13

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9 14,15

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12 Cetuximab18

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Bonomi P, Kim K, Fairclough D, et al. Comparison of survival and quality of life in advancednon-small cell lung cancer patients treated with two dose levels of paclitaxel combined withcisplatin versus etoposide with cisplatin:results of an Eastern Cooperative Oncology Grouptrial. J Clin Oncol 2000;18:623-631.

Ohe Y, Ohashi Y, Kubota K, et al. Randomized phase III study of cisplatin plus irinotecanversus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbinefor advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol2007;18:317-323..

Belani CP, Larocca RV, Rinaldi WJ, et al. A multicenter, phase III randomized trial for stageIIIB/IV NSCLC of weekly paclitaxel and carboplatin vs. standard paclitaxel and carboplatingiven every three weeks, followed by weekly paclitaxel. Proc Am Soc Clin Oncol2004;23:619[abstract 7017].

Hanna NH, Sheperd FA, Fossella FV, et al. Randomized phase III study of pemetrexedversus docetaxel in patients with non-small cell lung cancer previously treated withchemotherapy. J Clin Oncol 2004;22:1589-1597.

Shepherd FA, Pereira JR, Ciuleanu T, et al. Erlotinib in previously treated non-small-celllung cancer. N Engl J Med 2005;353(2):123-32.Sandler AB, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab fornon-small cell lung cancer. N Engl J Med 2006;355:2542-2550.

Green M, Manikhas G, Orlov S, et al. Abraxane , a novel Cremophor -free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer.Ann Oncol 2006;17(8):1263-1268.Rizvi N, Riely G, Azzoli, C, et al. Phase I/II Trial of Weekly Intravenous 130-nm Albumin-Bound Paclitaxel As Initial Chemotherapy in Patients With Stage IV Non–Small-Cell LungCancer. J Clin Oncol 2008;26:639-643.

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Wozniak AJ, Crowley JJ, Balcerzak SP, et al. Randomized trial comparing cisplatin withcisplatin plus vinorelbine in the treatment of advanced non-small cell lung cancer: ASouthwest Oncology Group Study. J Clin Oncol 1998;16:2459-2465.Cardenal F, Lopez-Cabrerizo MP, Anton A, et al. Randomized phase III study ofgemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced ormetastatic non-small cell lung cancer. J Clin Oncol 1999;17:12-18.Bellani CP, Lee JS, Socinski MA, et al. Randomized phase III trial comparing cisplatin-etoposide to carboplatin-paclitaxel in advanced or metastatic non-small cell lung cancer.Ann Oncol 2005;16(7):1069-1075Sandler AB, Nemunaitis J, Denham C, et al. Phase III trial of gemcitabine plus cisplatinversus cisplatin alone in patients with locally advanced or metastatic non-small cell lungcancer. J Clin Oncol 2000;18:122-130.Smit EF, van Meerbeeck JP, Lianes P, et al. Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: aphase III trial of the European Organization for Research and Treatment of Cancer LungCancer Group-EORTC 08975. J Clin Oncol 2003;21(21):3909-3917.Fossella F, Periera JR, von Pawel J, et al. Randomized, mutlinational, phase III study ofdocetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003;21(16):3016-3024.Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens foradvanced non-small cell lung cancer. N Engl J Med 2002;346:92-98.

Kelly K, Crowley J, Bunn PA, et al. Randomized phase III trial of paclitaxel plus carboplatinversus vinorelbine plus cisplatin in the treatment of patients with advanced non-small celllung cancer: A Southwest Oncology Group trial. J Clin Oncol 2001;19:3210-3218.

Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versusvinorelbine or ifosfamide in patients with advanced non-small cell lung cancer previouslytreated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell LungCancer Study Group. J Clin Oncol 2000;18:2354-2362.Pujol JL, Breton JL, Gervais R, et al. Gemcitabine-docetaxel versus cisplatin-vinorelbine inadvanced or metastatic non-small-cell lung cancer: a phase III study addressing the case forcisplatin. Ann Oncol 2005;16:602-610. Epub 2005 Mar 1.

Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plusgemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage NSCLC. J Clin Oncol 2008;26(21):3543-3551.

Pirker R, Periera JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients withadvanced non-small-cell lung cancer (FLEX): an open label randomised phase III trial.Lancet 2009;373:1525-1531.

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Albumin-bound paclitaxel may be substituted for either paclitaxel or docetaxel in patients whohave experienced hypersensitivity reactions after receiving paclitaxel or docetaxel despitepremedication, or for patients where the standard premedications (dexamethasone, H2blockers, H1 blockers) are contraindicated.




Agents listed below are used in the treatment of patients with NSCLC. Most are used in combination,

while others are used as monotherapy (eg, maintenance or second-line therapy).



Guidelines Index



CANCER SURVIVORSHIP CARE

Cancer Survivorship

NSCLC long term follow-up care

Resources

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In 2000, the prevalence of living cancer survivors with a diagnosis wasBreast cancer: 2,197,000Prostate cancer: 1,637,000Colon cancer: >1,000,000Lung cancer: 340,000

Cancer SurveillanceHistory and Physical and a contrast-enhanced chest CT scan every 4-6 months for 2 years (category 2B), then H&P and a non-contrast-

enhanced chest CT scan annually (category 2B)Smoking status assessment at each visit, counseling and referral for cessation as needed.

ImmunizationsAnnual Influenza vaccinationPneumococcal vaccination with revaccination as appropriate

National Cancer Institute Facing Forward: Life After Cancer Treatment

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Counseling Regarding Health Promotion and Wellness

Additional Health Monitoring

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Maintain a healthy weight

Adopt a physically active lifestyle (Regular physical activity: 30 minutes of moderate intensity physical activity on most days of the week)

Consume a healthy diet with emphasis on plant sources

Limit consumption of alcohol if you consume alcoholic beverages

Routine blood pressure, cholesterol and glucose monitoring

Bone health: Bone density testing as appropriate

Dental health: Routine dental examinations

Routine sun protection

http://www.cancer.gov/cancertopics/life-after-treatment/allpages



1Gloeckler Ries LA, Reichman ME, Riedel Lewis D, et al. Cancer survival and incidence from the surveillance, epidemiology, and end results (SEER) program. TheOncologist 2003; 8;541-552.

2ACS Guidelines on Nutrition and Physical Activity for Cancer Prevention( Accessed November 18, 2009)http://www.cancer.org/docroot/PED/content/PED_3_2X_Diet_and_Activity_Factors_That_Affect_Risks.asp?sitearea=PED

NSCL-G1 of 2



Guidelines Index



Cancer Screening Recommendations3,4

These recommendations are for average risk individuals and high risk patients should be individualized.

Colorectal Cancer: For men and women, Colonoscopy every 10 years (preferred) or fecal occult blood test (FOBT) annually and flexible

sigmoidoscopy every 5 years, beginning at age 50

Prostate Cancer: For men-annual prostate specific antigen (PSA) testing beginning at age 50; for African American males and those with

family history of prostate cancer, PSA testing beginning at age 40.

Breast Cancer: For women-monthly self breast exam (SBE) beginning at age 20 (optional); annual clinical breast exam (CBE) beginning at

age 25; annual mammogram beginning at age 40.

Cervical Cancer: Annual cervical cytology testing for women up to age 30; after age 30, annual cervical cytology testing or cervical cytology

testing every 2-3 years (if 3 negative/satisfactory annual cervical cytology tests) or cervical cytology and HPV-DNA testing. If both negative,

testing every 3 years.

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See NCCN Colorectal Cancer Screening Guidelines

See NCCN Prostate Cancer Early Detection Guidelines

See NCCN Breast Cancer Screening Guidelines

See NCCN Cervical Cancer Screening Guidelines

NON-SMALL CELL LUNG CANCER SURVIVORSHIP



NSCL-G2 of 2

3

4Memorial Sloan-Kettering Cancer Center Screening Guidelines: (Accessed November 24, 2009)

American Cancer Society Guidelines for Early Detection of Cancer:

(Accessed November 24, 2009)

http://www.mskcc.org/mskcc/html/65279.cfm

http://www.cancer.org/docroot/PED/content/PED_2_3X_ACS_Cancer_Detection_Guidelines_36.asp?sitearea=PED



Guidelines Index



Staging

ST-1

Table 6. Definitions for T, N, M*

T Primary TumorN Regional Lymph Nodes

M Distant Metastasis

TX Primary tumor cannot be assessed, or tumor proven by thepresence of malignant cells in sputum or bronchial washings but

not visualized by imaging or bronchoscopyT0 No evidence of primary tumorTis Carcinoma in situ

T1 Tumor 3 cm in greatest dimension, surrounded by lung orvisceral pleura, without bronchoscopic evidence of invasion more

proximal than the lobar bronchus (i.e., not in the main bronchus)

T1a Tumor 2 cm in greatest dimension

T1b Tumor > 2 cm but 3 cm in greatest dimension

T2 Tumor > 3 cm but 7 cm or tumor with any of the followingfeatures

Involves main bronchus, 2 cm distal to the carinaInvades visceral pleuraAssociated with atelectasis or obstructive pneumonitis thatextends to the hilar region but does not involve the entire lung

T2a Tumor > 3 cm but 5 cm in greatest dimension

T2b Tumor > 5 cm but 7 cm in greatest dimensionT3 Tumor > 7 cm or one that directly invades any of the following:

chest wall (including superior sulcus tumors), diaphragm, phrenic

nerve, mediastinal pleura, parietal pericardium; or tumor in the

main bronchus < 2 cm distal to the carina but without

involvement of the carina; or associated atelectasis or obstructive

pneumonitis of the entire lung or separate tumor nodule(s) in the

same lobeT4 Tumor of any size that invades any of the following:

mediastinum, heart, great vessels, trachea, recurrentlaryngeal nerve, esophagus, vertebral body, carina;separate tumor nodule(s) in a different ipsilateral lobe

NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar

lymph nodes and intrapulmonary nodes, includinginvolvement by direct extension

N2 Metastasis in ipsilateral mediastinal and/or subcarinal

lymph node(s)N3 Metastasis in contralateral mediastinal, contralateral hilar,

ipsilateral or contralateral scalene, or supraclavicularlymph node(s)

MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis

M1a Separate tumor nodule(s) in a contralateral lobe; tumor

with pleural nodules or malignant pleural (or pericardial)

effusionM1b Distant metastasis

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a

b

c

The uncommon superficial spreading tumor of any size with its invasivecomponent limited to the bronchial wall, which may extend proximally to themain bronchus, is also classified as T1.

T2 tumors with these features are classified T2a if 5 cm or if size cannot be

determined, and T2b if > 5 cm but 7 cm

Most pleural (and pericardial) effusions with lung cancer are due to tumor. In afew patients, however, multiple cytopathologic examinations of pleural(pericardial) fluid are negative for tumor, and the fluid is nonbloody and is notan exudate. Where these elements and clinical judgment dictate that theeffusion is not related to the tumor, the effusion should be excluded as astaging element and the patient should be classified as T1, T2, T3, or T4.

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*Used with permission. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: Proposals for the revision of the TNM stage groupings in theforthcoming (seventh) edition of the TNM classification of malignant tumors. J Thorac Oncol 2007;2:706-714.



Guidelines Index



ST-2

StagingTable 7. Descriptors, T and M Categories, and Stage Grouping*

Sixth Edition 7th Edition N0 N1 N2 N3T/M Descriptor T/M

IIA

IIA

IIB IIIA

IIB IIIA IIIA

IIIA IIIA

IIIA IIIA IIIB IIIB

IV IV IV IV

Cells in bold indicate a change from the sixth edition for a particular TNM category.

T1 (less than or equal to 2 cm) T1a IA IIA IIIA IIIB

T1 (>2–3 cm) T1b IA IIA IIIA IIIB

T2 (less than or equal to 5 cm) T2a IB IIIA IIIB

T2 (>5–7 cm) T2b IIB IIIA IIIB

T2 (> 7 cm) T3 IIIA IIIB

T3 invasion IIB IIIA IIIA IIIB

T4 (same lobe nodules) IIIB

T4 (extension) T4 IIIB IIIB

M1 (ipsilateral lung)

T4 (pleural effusion) M1a

M1 (contralateral lung) IV IV IV IV

M1 (distant) M1b IV IV IV IV

*Used with permission. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: Proposals for the revision of the TNM stage groupings in theforthcoming (seventh) edition of the TNM classification of malignant tumors. J Thorac Oncol 2007;2:706-714.

Version 2.2010, 03/05/10 © 2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-1

Guidelines IndexNSCL Table of Contents

Staging, Discussion, ReferencesPractice Guidelinesin Oncology – v.2.2010 Non-Small Cell Lung Cancer

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NCCNDiscussion

NCCN Categories of Evidence and Consensus

Category 1: The recommendation is based on high-level evidence (e.g. randomized controlled trials) and there is uniform NCCN consensus.

Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus.

Category 2B: The recommendation is based on lower-level evidence and there is nonuniform NCCN consensus (but no major disagreement).

Category 3: The recommendation is based on any level of evidence but reflects major disagreement.

All recommendations are category 2A unless otherwise noted.

Overview Lung cancer is the leading cause of cancer death in the United States. An estimated 219,440 new cases (116,090 in men and 103,350 in women) of lung and bronchus cancer will be diagnosed in 2009, and 159,390 deaths (88,900 in men, 70,490 in women) are estimated to occur due to the disease.1 Only 15% of all lung cancer patients are alive 5 years or more after diagnosis (http://seer.cancer.gov/statfacts/html/lungb.html). Common symptoms of lung cancer include cough, dyspnea, weight loss, and chest pain; symptomatic patients are more likely to have chronic obstructive pulmonary disease.

The primary risk factor for lung cancer is smoking, which accounts for more than 85% of all lung cancer-related deaths.2 The risk of lung cancer increases with the number of cigarettes smoked per day and

with the number of years spent smoking. In addition to the hazard of first-hand smoke, exposed nonsmokers have an increased relative risk of developing lung cancer.3 Radon gas, a radioactive gas that is produced by the decay of radium 226, is the second leading cause of lung cancer.4 The decay of this isotope leads to the production of substances that emit alpha-particles, which may cause cell damage and, therefore, increase the potential for malignant transformation. Data suggest that postmenopausal women who smoke or are former smokers should not receive hormone replacement therapy, because it increases the risk of death from non-small cell lung cancer (NSCLC).5

Asbestos, a mineral compound that breaks into small airborne shards, is a known carcinogen that increases the risk of lung cancer in people exposed to airborne fibers, especially in individuals who smoke. It is estimated that about 3% to 4% of lung cancers are caused by asbestos exposure.6 In addition, other possible risk factors include recurring lung inflammation, lung scarring secondary to tuberculosis, family history, and exposure to other carcinogens (i.e., bis(chloromethyl)ether, polycyclic aromatic hydrocarbons, chromium, nickel, and organic arsenic compounds).7,8

Prevention and Screening Lung cancer is a unique disease, because the etiologic agent is an industry and more than 85% of cases are caused by voluntary or involuntary “second-hand” cigarette smoking. Active smoking and second-hand smoke both cause lung cancer (see Reports from the Surgeon General, which are the next 2 links). There is a causal relationship between active smoking and lung cancer and also with other cancers, such as esophageal, oral, laryngeal, pharyngeal, and cervical cancers (http://www.cdc.gov/tobacco/data_statistics/sgr/2004/pdfs/executivesummary.pdf). Smoking harms nearly every organ in the body. Those who live with someone who smokes have a 20% to 30% increased risk for




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NCCNlung cancer (http://www.surgeongeneral.gov/library/secondhandsmoke/report/executivesummary.pdf).

Further complicating this problem, cigarettes also contain the highly addictive substance nicotine. Oncologists should encourage smoking cessation, especially in patients with cancer (http://www.smokefree.gov/). Programs using behavioral counseling combined with medications that promote smoking cessation (approved by the FDA [Food and Drug Administration]) can be very useful (see Treating Tobacco Use and Dependence: 2008 Update, which is published by the Agency for Healthcare Research and Quality [AHRQ]) (http://www.surgeongeneral.gov/tobacco/treating_tobacco_use08.pdf).

Varenicline is a new class of drug for smoking cessation; other drugs include nicotine replacement (e.g., gum, inhaler, nasal spray, patch) and bupropion. Studies have shown that varenicline is better than bupropion for smoking cessation.9,10 However, almost 30% of patients had nausea while using varenicline.11 The effectiveness of varenicline for preventing relapse has not been clearly established.12 The FDA has issued an alert for varenicline regarding neuropsychiatric symptoms (http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm106540.htm).

Lung cancer is still the leading cause of cancer death worldwide, and late diagnosis is a fundamental obstacle to improving lung cancer outcomes.13,14 Because localized cancer can be managed curatively and because survival in other solid tumors (e.g., breast, cervix, colon, and prostate) appears to be increased by screening and early detection, lung cancer would be an appropriate candidate for a population-based screening approach. Pilot trials of spiral computed tomography (CT) in lung cancer screening are promising with a frequency of stage I detectable lung cancer in more than 80% of newly diagnosed cases.15-17 The National Lung Screening Trial (NLST, ACRIN

Protocol A6654) is a randomized, controlled study involving 50,000 current or former smokers; this trial is assessing the risks and benefits of spiral CT scans compared with chest x-rays for detecting lung cancer. The NSLT is now closed; results are expected by 2011. Additional information on NLST can be found at http://www.cancer.gov/nlst.

The International Early Lung Cancer Action Program (I-ELCAP) has been assessing whether annual screening by spiral CT scan increases the detection of early-stage lung cancer in patients at risk for cancer. Data from I-ELCAP showed that stage I lung cancer can be detected using annual low-dose CT screening. The 10-year survival rate was 92% for stage I patients whose cancers were promptly removed; however, all stage I patients who chose not to be treated died within 5 years.18 Additional information on I-ELCAP can be found at http://www.ielcap.org/index.htm. Screening can increase the diagnosis of early-stage lung cancers and yields excellent survival data. However, whether mortality is decreased by screening has not yet been conclusively demonstrated and is expected to be answered by the NLST.

At the present time, the NCCN panel does not recommend the routine use of screening CT as standard clinical practice (category 3). Available data18-21 are conflicting;22,23 thus, conclusive data from ongoing trials are necessary to define the benefits and risks associated with screening for lung cancer with low-dose CT. The panel recommends that high-risk individuals participate in a clinical trial evaluating CT screening. If a trial is not available or if the high-risk individual is not eligible for a trial, then the individual should go to a center of excellence with expertise (in radiology, pathology, cytology, thoracic surgery, and general expertise in lung cancer treatment) to discuss the potential risks and benefits before having a screening CT.24 If a screening strategy is used, then the I-ELCAP screening protocol should be followed




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NCCN(http://www.ielcap.org/professionals/docs/ielcap.pdf). Data show that a CT screening clinic detected a malignant tumor in 3% of patients; many patients (45%) did not complete followup.25

Classification and Prognostic Factors The World Health Organization divides lung cancer into 2 major classes based on its biology, therapy, and prognosis: NSCLC (discussed in this guideline) and small cell lung cancer ([SCLC], see NCCN Small Cell Lung Cancer Guideline). NSCLC accounts for more than 85% of all lung cancer cases, and it includes 2 major types: (1) non-squamous carcinoma (including adenocarcinoma, large-cell carcinoma, other cell types); and (2) squamous cell (epidermoid) carcinoma. Adenocarcinoma is the most common type of lung cancer seen in the United States and is also the most frequently occurring cell type in nonsmokers. Gene expression profiling (using DNA microarrays) has identified subtypes of lung adenocarcinomas (i.e., bronchioid, squamoid, magnoid), which correlate with stage-specific survival and metastatic pattern. Bronchioid tumors were associated with increased survival in early-stage disease, whereas, squamoid tumors were associated with increased survival in advanced disease.26

Certain prognostic factors are predictive of survival in patients with NSCLC. Good prognostic factors include early-stage disease at diagnosis, good performance status ([PS] Eastern Cooperative Oncology Group 0, 1, or 2), no significant weight loss (not more than 5%), and female gender.27 Age and histologic subtype have little prognostic significance. Biologic prognostic factors, including mutations of the tumor suppressor gene (p53), the activation of proto-oncogene Kirsten-Rous sarcoma virus (K-ras), and other biologic markers, may have significant value in predicting a poor prognosis.28,29 Patients with stage I lung adenocarcinoma who have specific genetic abnormalities, such as k-ras oncogene activation, have a poor prognosis and disease-free survival.

Pathologic Evaluation of Lung Cancer Pathologic evaluation is performed to classify the lung cancer, determine the extent of invasion, establish the cancer involvement status of the surgical margins, and determine the molecular abnormalities of lung cancer that may be able to predict for sensitivity and resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI).30-32 Preoperative evaluations include examination of one of the following specimens: bronchial brushings, bronchial washings, fine-needle aspiration (FNA) biopsy, core needle biopsy, endobronchial biopsy, and transbronchial biopsy. In addition, the mediastinal lymph nodes are sampled to assess the staging and therapeutic options.

Lobectomy or pneumonectomy specimens are evaluated intraoperatively to determine the surgical resection margin status, diagnose incidental nodules discovered at the time of surgery, or evaluate the regional lymph nodes. Postoperative evaluation provides the pathology characteristics necessary for the classification of tumor type, staging, and prognostic factors. The surgical pathology report should include the histologic classification published by the World Health Organization for carcinomas of the lung.33 The principles of pathology review are listed in NSCL-A.

Bronchioloalveolar Carcinoma Bronchioloalveolar carcinoma (BAC) is an important subtype of pulmonary adenocarcinoma;34 data suggest that gefitinib and erlotinib are useful for patients with BAC.35-37 BAC includes only noninvasive tumors where the neoplastic cells spread out along pre-existing alveolar structures (lepidic spread). Pure BAC requires absence of invasion of stroma, pleura, or lymphatic spaces.38 BAC is divided into 3 subtypes: 1) mucinous, 2) nonmucinous, and 3) a mixed mucinous and nonmucinous or indeterminate form. Nonmucinous BAC expresses the thyroid transcription factor-1 (TTF-1). Mucinous BACs express CK20




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NCCNand CK7, but reportedly lack TTF-1 expression.39 BACs are usually CK7+ and CK20- and therefore distinguishable from CK7- and CK20+ metastatic adenocarcinoma of the colorectum. Mucinous BACs are often CK7+/CK20+.40 CDX-2 is a highly sensitive and specific marker of adenocarcinomas of intestinal origin that could be used to distinguish mucinous BAC from metastatic primary gastrointestinal cancers.

Immunohistochemical Staining Immunohistochemistry is most valuable in distinguishing between malignant mesothelioma and lung adenocarcinoma. A panel of 4 markers, 2 positive in mesothelioma and 2 negative in mesothelioma (but positive in adenocarcinoma) are used routinely. The stains that are negative in mesothelioma, but positive in adenocarcinoma, are CEA (carcinoembryonic antigen), B72.3, Ber-EP4, and MOC31. Stains that are sensitive and specific for mesothelioma include WT-1, calretinin, D2-40,41 and cytokeratin 5/6. Immunostains are used to differentiate primary pulmonary adenocarcinoma from metastatic adenocarcinoma to the lung, to distinguish adenocarcinoma from malignant mesothelioma, and to determine the neuroendocrine status of tumors. TTF-1 is a homeodomain-containing transcription factor that regulates tissue-specific expression of surfactant apoprotein A (SPA), surfactant apoprotein B (SPB), surfactant apoprotein C (SPC), Clara cell antigen, and T1α.

TTF-1 is very important in distinguishing primary from metastatic adenocarcinoma, because most primary carcinomas are TTF-1 positive, whereas metastatic adenocarcinomas to the lung (e.g., from breast cancer) are usually TTF-1 negative. However, TTF-1 is positive in tumors from patients with thyroid cancer.42 In addition, thyroglobulin is present in tumors from patients with thyroid cancer, while it is negative in lung cancer tumors. Pulmonary adenocarcinoma of the lung is usually CK7+ and CK20- and therefore distinguishable from CK7- and CK20+ metastatic adenocarcinoma of the colorectum. CDX-2 is a

highly specific and sensitive marker for metastatic gastrointestinal malignancies that could be used to differentiate them from primary lung tumors. Neuroendocrine tumors of the lung are diagnosed with chromogranin (reacts with cytoplasmic neuroendocrine granules) and synaptophysin (reacts with a cell membrane glycoprotein). All typical and atypical carcinoid tumors stain with chromogranin and synaptophysin, whereas small cell lung carcinoma is negative in 25% of the cases.

Nearly all SCLCs are immunoreactive for keratin, epithelial membrane antigen, and TTF-1. Many SCLCs also stain positively for markers of neuroendocrine differentiation, including chromogranin A, neuron-specific enolase, neural cell adhesion molecule (NCAM), and synaptophysin. However, these markers alone cannot be used to distinguish SCLC from NSCLC, because approximately 10% of NSCLCs are immunoreactive for at least one of these neuroendocrine markers.43

Staging The international staging system for lung cancer has been revised and adopted by the American Joint Committee on Cancer (AJCC) and by the Union Internationale Contre le Cancer.44-47 A new lung cancer staging system has been proposed by the International Association of the Study of Lung Cancer (IASLC).48,49 The revised staging is available from the AJCC (7th edition).50 These NCCN guidelines have been updated with the new AJCC (7th edition) staging revisions. The revised stage grouping is summarized in Table 6 of the staging tables. The descriptors of the TNM classification scheme are summarized in Table 7 (note that the cells in bold indicate a change from the 6th edition for a particular TNM category).

The new TNM staging revisions take effect for all new cases diagnosed after January 1, 2010.50 With the new staging, locally advanced disease




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NCCNis now stage III; advanced disease is now stage IV. The revised AJCC staging for 2010 includes upstaging and downstaging: for example,1) T2bN0M0 is upstaged from stage IB to stage IIA; 2) T2aN1M0 is downstaged from stage IIB to stage IIA; 3) T4N0-N1M0 is downstaged from stage IIIB to stage IIIA; and 4) wet IIIB (i.e., malignant pleural effusions) is upstaged to stage IV.51 These new changes reflect the prognosis of patients with these different tumors.

Pathologic staging uses both clinical staging information (which is noninvasive and includes medical history, physical examination, imaging) and other invasive staging procedures (i.e., thoracotomy, mediastinoscopy examination of resected lymph nodes).44

For 1996-2004, the overall 5-year relative survival rate for lung cancer was 15.2% (from 17 SEER [Surveillance, Epidemiology, and End Results] geographic areas in the United States). Of lung and bronchus cancer cases, 16% were diagnosed while the cancer was still confined to the primary site (localized stage); 25% were diagnosed after the cancer had spread to regional lymph nodes or directly beyond the primary site; 51% were diagnosed after the cancer had already metastasized (distant stage); and for the remaining 8%, the staging information was unknown. The corresponding 5-year relative survival rates were: 49.5% for localized, 20.6% for regional, 2.8% for distant, and 8.3% for unstaged (http://seer.cancer.gov/statfacts/html/lungb.html). However, these data include small cell lung cancer, which has a poorer prognosis. Five-year survival after lobectomy for pathologic stage I NSCLC ranges from 45% to 65%, depending on whether the patient is stage 1A or 1B and on the location of the tumor.52 Another study in stage I patients (n=19,702) found that 82% had surgical resection and their 5-year overall survival was 54%; however, for untreated stage I NSNCL, 5-year overall survival was only 6%.53 Of stage I patients who refused surgery

(although it was recommended), 78% died of lung cancer within 5 years.

Prognostic and Predictive Biomarkers Several biomarkers have emerged as prognostic and predictive markers for NSCLC. Among these biomarkers, the evidence is strongest for epidermal growth factor receptor (EGFR), the 5’ endonuclease of the nucleotide excision repair complex (ERCC1), the k-ras oncogene, and the regulatory subunit of ribonucleotide reductase (RRM1). A prognostic biomarker is a biomolecule that is indicative of patient survival independent of the treatment received; that is, the biomolecule is an indicator of the innate tumor aggressiveness. A predictive biomarker is a biomolecule that is indicative of therapeutic efficacy; that is, there is an interaction between the biomolecule and therapy on patients’ outcome.

The presence of the EGFR exon 19 deletion or exon 21 L858R mutation does not appear to be prognostic of survival for patients with NSCLC, independent of therapy.54 However, the presence of the EGFR exon 19 deletion or exon 21 L858R mutation is predictive of treatment benefit from EGFR-TKI therapy.36,55 High ERCC1 levels are prognostic of better survival for patients with NSCLC when compared to low levels of ERCC1 expression, independent of therapy.56,57 High levels of ERCC1 expression are also predictive of poor response to platinum-based chemotherapy.57,58 The presence of K-ras mutations is prognostic of poor survival for patients with NSCLC when compared to absence of K-ras mutations, independent of therapy.28 Presence of K-ras mutations is also predictive of lack of benefit from platinum/vinorelbine chemotherapy or EGFR TKI therapy.36,59 High RRM1 levels are prognostic of better survival for patients with NSCLC compared to low levels of RRM1 expression, independent of therapy.60,61 High levels of RRM1 expression are also predictive of poor response to gemcitabine-based chemotherapy.58,62,63




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NCCNEGFR Mutations, Gene Copy Number, and Level of Expression EGFR is a transmembrane receptor. When EGF binds to the extracellular domain, receptor dimers are formed with activation of the intracellular tyrosine kinase domain. This results in autophosphorylation and in phosphorylation of downstream molecules with activation of multiple cellular functions including proliferation and survival. EGFR is detectable in approximately 80%-85% of patients with NSCLC, and the levels of expression vary widely on a continual scale.

Three different methods are currently used to determine the EGFR status in tumor cells. The methods include mutation analysis, gene copy number determination, and the level of EGFR expression. The most commonly found EGFR mutations are deletions in exon 19 (E19del) and a mutation in exon 21 (L858R). Both mutations result in activation of the tyrosine kinase domain, and both are associated with sensitivity to the small molecule TKIs, erlotinib and gefitinib. These mutations are found in approximately 10%-15% of Caucasian patients with NSCLC and in 30%-40% of Asian patients.

The prognostic effect of EGFR mutations E19del and L858R is not clear, because most reports are limited to patients receiving active therapy. Tsao and colleagues determined mutations in 177 patients who participated in a randomized trial of second-line gefitinib versus placebo.54 Mutations were found in 40 patients, and 20 had E19del or L858R. They did not find a correlation between mutational status and gene copy number or expression by standard immunohistochemistry. In the placebo-treated group, 19 patients had any EGFR mutation, and their overall survival was apparently not different from the 44 patients without mutations. A retrospective study of patients treated with first-line chemotherapy with or without erlotinib found that the median overall survival for all patients with mutations (N=11) was significantly better (>20 months, P<.001) than overall survival for patients without mutations (N=45, 10 months).31

The predictive effects of EGFR mutations E19del and L858R are well defined. Patients with these mutations have a significantly better response to erlotinib or gefitinib. The initial retrospective reports suggested that approximately 90% of patients with a tumor response to these drugs had mutations, whereas unresponsive patients did not have mutations.64,65 Subsequent retrospective studies have demonstrated an objective response rate of approximately 80% with a median progression-free survival of 13 months to single-agent therapy in patients with a bronchioloalveolar variant of adenocarcinoma and an EGFR mutation.36 A recent prospective study has demonstrated that the objective response rate in North American patients with non-squamous cell histology and EGFR mutations (53% E19del, 26% L858R, 21% other mutations) is 55% with a median progression-free survival of 9.2 months.55 In patients treated with first-line chemotherapy with or without erlotinib, EGFR mutations were predictive of a better response in patients receiving erlotinib (53% in patients with mutations versus 18% in those without mutations).31 The response rates in the group of patients receiving only chemotherapy were 21% for those with mutations and 27% for those without mutations.

ERCC1 Level of Expression ERCC1 is the 5’ endonuclease of the nucleotide excision repair complex. It is found in all tumor cells, and its level of expression varies widely. In patients with completely resected NSCLC who did not receive perioperative chemotherapy or radiation, ERCC1 mRNA levels were prognostic of survival. Patients whose tumors had high levels (N=26, relative ERCC1 expression above the cohort median of 50) lived significantly longer than patients whose tumors had low levels (N=25, relative expression below 50).56 These results were independently confirmed in a similar cohort of patients (N=372) using standard immunohistochemistry. Patients with high tumoral ERCC1 expression had a median overall survival of 55 months compared to 42 months for patients with low ERCC1 expression.57




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NCCNMultiple translational investigations have provided evidence for the predictive use of ERCC1 levels to assess the efficacy of platinum-based chemotherapies in NSCLC; high levels are associated with resistance, while low levels are associated with sensitivity. Initially, studies used semiquantitative determination of ERCC1 mRNA levels. Using prospectively collected fresh-frozen tumor samples, an association between ERCC1 mRNA levels and response to 2 cycles of gemcitabine and carboplatin was described.58 Tumors with low ERCC1 expression had a better response than tumors with high ERCC1 expression in 35 patients with inoperable, locally advanced NSCLC. In a retrospective analysis of tumor specimens from 56 patients with advanced NSCLC who were treated with gemcitabine and cisplatin, no significant correlation between disease response and ERCC1 mRNA levels was observed. However, overall survival was significantly longer in patients with low ERCC1 expression (14.2 months) when compared to patients with high expression (4.7 months).66

Olaussen and colleagues found that ERCC1 protein expression, as determined by standard immunohistochemistry, was predictive of benefit from adjuvant cisplatin-based therapy in a large group of patients with surgically resected NSCLC who participated in the International Adjuvant Lung Trial (IALT).57 In this study, only patients with low tumoral ERCC1 protein levels benefited from adjuvant chemotherapy (adjusted hazard ratio for death, 0.65; 95% CI, 0.50 to 0.86; P=.002). Most recently, Bepler and colleagues reported that in situ ERCC1 protein levels in tumor specimens collected prospectively from a community-based randomized phase III clinical trial were significantly and inversely correlated with disease response to carboplatin/gemcitabine or gemcitabine alone (P=.003, r=0.39); that is, response was better in patients with low levels of ERCC1 expression.62,63

K-ras Mutations K-ras is a GTP-binding protein and involved in G-protein coupled receptor signaling. In its mutated form, it is constitutively active, able to transform immortalized cells, and promotes cell proliferation and survival. Initially, K-ras was described as mutated in codon 12 in 5/10 adenocarcinomas and 0/15 squamous and 0/10 large cell carcinomas.67 Current data suggest that approximately 25% of adenocarcinomas in a North American population have K-ras mutations.31,36,59 K-ras mutation prevalence is associated with cigarette smoking.68

K-ras mutational status is prognostic of survival. Patients with K-ras mutations have a shorter survival than patients with wild-type K-ras. Slebos and colleagues determined K-ras codon 12 mutations in 69 patients with completely resected adenocarcinomas who did not receive additional therapy.28 They found that disease-free and overall survival were significantly (P=.038 and P=.002, respectively) shorter in the 19 patients with mutations compared to the 50 patients without mutations. These data were independently confirmed in a cohort of 66 patients (11 with K-ras codon 12 mutations; P=.03 for overall survival difference) by Mitsudomi and colleagues.69 However, Tsao and colleagues did not find a significant difference (P=.40) in survival by ras mutational status on the observation arm of the Canadian adjuvant chemotherapy trial (JBR10).59 In this report, the authors investigated codons 12, 13, and 61 of all 3 ras genes and categorized patients as ras mutated if any mutation was detected.

K-ras mutational status is also predictive of therapeutic efficacy from EGFR-TKIs; however, it does not appear to affect chemotherapeutic efficacy. In a retrospective study of 101 patients with a bronchioloalveolar variant of adenocarcinoma, K-ras codon 12 and 13 mutations were found in 23% (18/80) of patients.36 All patients had been treated with first-line single-agent erlotinib. None of the patients




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NCCNwith K-ras mutations responded (0/18), while 20 without K-ras mutations responded (20/62, 32%). This difference was statistically significant (P<.01). In patients treated with first-line chemotherapy plus erlotinib or chemotherapy plus placebo (the TRIBUTE trial), K-ras codon 12 and 13 mutations were present in 51/264 and 4/264 patients respectively.31 Patients with K-ras mutations had a response rate of 8% in the chemotherapy plus erlotinib arm (2/25) and 23% in the chemotherapy only arm (7/30). Patients without K-ras mutations had a response rate of 26% in the chemotherapy plus erlotinib arm (27/104) and 26% in the chemotherapy only arm (27/103). In this report, time-to-progression and overall survival were also shortest in the group of patients with K-ras mutations receiving chemotherapy plus erlotinib, which suggests that the addition of erlotinib to chemotherapy in patients with K-ras mutations may adversely interfere with chemotherapeutic efficacy.

Tsao and colleagues identified 88 patients with and 333 without any ras mutation (codons 12, 13, and 61 of K-ras, N-ras, H-ras) in the Canadian adjuvant chemotherapy trial (JBR10).59 They found that patients with ras mutations did not derive benefit from adjuvant cisplatin/vinorelbine (hazard ratio of death for chemotherapy versus observation 0.95, CI, 0.53-1.71; P=.87), while those without ras mutations (N=333) benefited significantly (hazard ratio of death for chemotherapy versus observation 0.69, CI, 0.49-0.97; P=.03) from adjuvant therapy. However, when taking both the treatment arm and the ras mutational status into account (i.e., when testing for interaction), the P-value did not reach statistical significance (P=.29).

RRM1 Level of Expression RRM1 is the gene that encodes the regulatory subunit of ribonucleotide reductase, and it is crucial for production of deoxynucleotides from nucleotides.70,71 RRM1 is found in all tumor cells, and its level of expression varies widely over a continuous range.

In patients with completely resected NSCLC who did not receive perioperative chemotherapy or radiation, RRM1 mRNA levels were prognostic of survival. Patients whose tumors had high levels (N=39, relative RRM1 expression above the cohort median of 12.2) lived significantly longer than patients whose tumors had low levels (N=38, relative expression below 12.2).60 These results were independently confirmed in a cohort of 187 patients with stage I disease. Patients with high tumoral RRM1 expression had a median overall survival of greater than 120 months compared to 60.2 months for patients with low RRM1 expression.61

In fresh frozen tumor specimens that had been prospectively collected on patients treated with gemcitabine and carboplatin, RRM1 expression levels were predictive of tumor response. Tumors with low RRM1 expression responded significantly better to treatment than tumors with high levels of expression.58 In addition, RRM1 mRNA levels were significantly associated with overall survival in patients with advanced stage NSCLC who were treated with gemcitabine and cisplatin.72 In this analysis, patients with low RRM1 levels had a median overall survival of 13.7 months while patients with high levels had a median overall survival of 3.6 months. The addition of a vinca alkaloid to a gemcitabine regimen abolished the effect of RRM1 expression on overall survival, which suggests that a substantial interaction exists between the biomarker and treatment regimen on patient outcome.

Most recently, Bepler and colleagues reported that in situ RRM1 protein levels in tumor specimens collected prospectively from a community-based randomized phase III clinical trial were significantly and inversely correlated with disease response to gemcitabine or carboplatin/gemcitabine (P=0.001, r=0.41); that is, response was better in patients with low levels of RRM1 expression.62,63




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NCCNTreatment Approaches Surgery, radiation therapy (RT), and chemotherapy are the 3 modalities commonly used to treat patients with NSCLC. They can be used either alone or in combination depending on the disease status. In the following sections, the clinical trials are described that have led to the standard treatments.

Surgery In general, for patients with stage I or stage II disease, surgery provides the best chance for cure. However, thoracic surgical oncology consultation should be part of the evaluation of any patient being considered for curative local therapy.

The overall plan of treatment and the necessary imaging studies should be determined before any nonemergency treatment is initiated. Determination of resectability, surgical staging, and pulmonary resection should be performed by board-certified thoracic surgeons who perform lung cancer surgery as a prominent part of their practice. Thoracic surgeons should actively participate in multidisciplinary discussions and meetings regarding lung cancer patients (e.g., multidisciplinary clinic and/or Tumor Board). Patients with pathologic stage II or greater should be referred to medical oncology for evaluation. Consider referral to medical oncologist for patients with stage IB and consider referral to radiation oncologist for stage IIIA. Treatment delays because of poor coordination among specialists should be avoided.

The surgical procedure used depends on the extent of disease and on the cardiopulmonary reserve of the patient. Lung-sparing anatomic resection (sleeve lobectomy) is preferred over pneumonectomy, if anatomically appropriate and if margin-negative resection can be achieved; otherwise, lobectomy or pneumonectomy should be done if physiologically feasible.73,74 Resection (including wedge resection) is

preferred over ablation (i.e., radiofrequency ablation, cryotherapy, stereotactic radiation).74 However, it is controversial whether lung-sparing surgeries (i.e., sublobular resection), such as segmentectomy and wedge resection, are useful in patients with severely reduced pulmonary function who are otherwise not candidates for surgery.74-76

The American College of Surgeons Oncology Group is conducting a randomized trial (ACOSOG Z0030) of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in patients with N0 (no demonstrable metastasis to regional lymph nodes) or N1 (metastasis to lymph nodes in the ipsilateral peribronchial and/or hilar region, including direct extension) NSCLC disease. This study is evaluating whether complete mediastinal lymph node dissection results in better overall survival when compared to mediastinal lymph node sampling in the patient undergoing resection for N0 or non-hilar N1 NSCLC. Initial results indicate that morbidity is not increased with complete lymphadenectomy.77,78

Patients should have N1 and N2 node resection and mapping (American Thoracic Society map) with a minimum of 3 N2 stations sampled or a complete lymph node dissection. Note that the IASCL (International Association for the Study of Lung Cancer) has recently proposed a new lymph node map.79 Formal ipsilateral mediastinal lymph node dissection is indicated for patients undergoing resection for stage IIIA (N2) disease. For patients undergoing sublobular resection, the appropriate N1 and N2 lymph node stations should be sampled unless not technically feasible because it would substantially increase the surgical risk.

Sublobular resection, either segmentectomy (preferred) or wedge resection, is appropriate in selected patients:1) those who are not eligible for lobectomy because of poor pulmonary reserve or other major co-morbidity; and 2) those with a peripheral nodule 2 cm or less with at least one of the following (pure BAC histology [category 2B],




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NCCNnodule has 50% or more ground glass appearance on CT [category 2B], and/or radiologic surveillance confirms a doubling time of 400 days or more [category 2B]). Segmentectomy (preferred) or wedge resection should achieve parenchymal resection margins 1) 2 cm or more, or 2) the size of the nodule or more.80,81

Video-assisted thoracic surgery (VATS) is a relatively new minimally invasive surgical treatment that is currently being investigated in all aspects of lung cancer.82,83 Published studies suggest that VATS has several advantages over the standard thoracotomy (or pleurotomy).84-88 Acute and chronic pain associated with VATS is minimal; thus, this procedure requires shorter length of hospitalization.89 VATS is also associated with low postoperative morbidity and mortality, minimal risk of intraoperative bleeding, or minimal locoregional recurrence.90-94

In stage I NSCLC patients who have VATS with lymph node dissection, the 5-year survival rate, long-term survival, and local recurrence were comparable to those achieved by routine open lung resection.95-97 VATS has also been shown to improve discharge independence in older populations and in high-risk patients as well.98,99 Recent data show that VATs improves the ability of patients to complete postoperative chemotherapy regimens.100,101 Based on its favorable effects on postoperative recovery and morbidity, VATS is included in the guidelines (see NSCL-B) as a reasonable and acceptable approach for patients who are surgically resectable with no anatomic or surgical contraindications as long as standard oncologic and dissection principles of thoracic surgery are not compromised.

Radiation Therapy General Principles Radiation therapy can be used as 1) an adjunct for patients with resectable NSCLC who have no contraindications for surgery; 2) the primary local treatment (i.e., definitive RT) for patients with medically

inoperable or unresectable NSCLC; and/or 3) an important palliative modality for patients with incurable NSCLC. The terminology and abbreviations for RT are described in the algorithm (see Table 1). Treatment recommendations should be made after joint consultation and/or discussion by a multidisciplinary team including surgical oncologists, radiation oncologists, medical oncologists, pulmonologists, pathologists, and diagnostic radiologists.

For resected tumors with pathologic mediastinal nodal involvement (pN2) and negative surgical margins, adjuvant chemotherapy (category 1) followed by postoperative radiotherapy is preferred, although the sequencing between radiation and chemotherapy in this setting has not been established (see NSCL-3 and NSCL-7).102-104 For patients with negative margins, most NCCN institutions give sequential chemotherapy/RT. For tumors with pN2 and positive resection margins, postoperative concurrent chemoradiation is recommended if the patient is medically fit.105,106 Radiation therapy should start earlier, because local recurrence is the most common failure in this group of patients.107

Conformal RT with or without chemotherapy should be offered to patients with curable stage I-III NSCLC who are medically inoperable but have reasonable performance status and life expectancy.108 Modern 3-dimensional conformal RT techniques with CT or CT/positron emission tomography (PET)--based treatment planning should be used on all patients. Both treatment outcome and cost should be considered. In patients receiving RT or chemoradiation with curative intent, treatment interruptions or dose reductions for manageable acute toxicities (i.e., grade 3 esophagitis, hematologic toxicities) should be minimized by conformal treatment planning and aggressive supportive care. RT can be offered to primary or distant sites as palliative care for stage IV patients with extensive metastases.

To avoid postoperative pulmonary toxicity, preoperative chemoradiotherapy should be avoided if at all possible, if




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NCCNpneumonectomy is required.109,110 Surgery in a field that has had 60 Gy is difficult, because the landmarks disappear with high doses of radiation. Thus, surgeons are often wary of resection in areas that have previously received RT doses of more than 45 Gy, especially patients who have received RT doses of more than 60 Gy (i.e., patients who have received definitive concurrent chemoradiation). Therefore, the radiation dose should be carefully considered if patients might be eligible for surgery. Radiation therapy should continue to definitive dose without interruption if the patient is not a surgical candidate.

Dose, Volume and Normal Tissue Constraints for Conventionally Fractionated RT The dose recommendations for definitive and palliative RT are summarized in the algorithm (see Table 2). Tissue heterogeneity correction should be used in RT treatment planning for all patients. Preoperatively, a dose of 45-50 Gy in 1.8 to 2 Gy fraction size is often recommended.111 Doses greater than 50 Gy in the preoperative setting have been reported to be safe and achieved favorable survival outcome;112-114 however, this should only be performed with an experienced team.

The postoperative RT dose should be based on margin status. After surgery, lung tolerance to RT is remarkably smaller than for patients with intact lungs. Every effort should be made to minimize the [postoperative] dose of RT. Although the dose volume constraints for normal lungs are a useful guide, more conservative constraints should be used for postoperative RT (see Table 3).For definitive RT, the commonly prescribed dose is 60-70 Gy.115 A dose of 74 Gy or more was associated with better survival in patients treated with radiation alone or with sequential chemotherapy followed by radiation in a retrospective study.116 The radiation dose is one significant factor for overall survival in patients with stage I-II after radiation alone117 or stage III disease treated with concurrent chemoradiation.118 When radiation is

given concurrently with chemotherapy, a dose up to 74 Gy may be delivered safely,119-121 if the dose to normal structures is strictly limited (see Table 3). The role of high-dose radiation with concurrent chemotherapy is currently being tested in a phase III randomized trial (RTOG 0617).

For treatment volume consideration, planning target volume (PTV) should be defined per the ICRU-62 (International Commission on Radiation Units and Measurements Report 62) guidelines, based on gross tumor volume (GTV), plus clinical target volume (CTV) margins for microscopic diseases, internal target volume (ITV) margins for target motion, and margins for daily set-up errors.122 GTV should be confined to visible tumors (include both primary and nodal diseases) on CT or PET-CT.

In patients who receive postoperative radiotherapy, CTV should consist of the bronchial stump and high-risk draining lymph node stations.123

Regarding CTV of nodal regions, elective nodal irradiation (ENI) remains controversial124 and should be individualized based on tumor volume, dosimetric parameters of adjacent normal structures, and comorbid conditions. Involved field radiation to high dose without ENI has been shown to allow higher dose radiation with acceptable toxicity and low risk of isolated nodal relapse.115,116,125-128

It is essential to evaluate the dose volume histogram (DVH) of critical structures and to limit the doses to the spinal cord, lungs, heart, esophagus, and brachial plexus to minimize normal tissue toxicity (see Table 3). These limits are largely empirical.129-136 For patients receiving postoperative RT, more strict DVH parameters should be considered for lung. The exact limit is unknown for lobectomy cases; mean lung dose should be limited to less than 8.5 Gy in pneumonectomy patients.




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NCCNRadiation Simulation, Planning and Delivery Treatment planning should be based on CT scans obtained in the treatment position. IV contrast should be used for better target delineation whenever possible, especially in patients with central tumors or with nodal diseases. PET/CT is preferable in cases with significant atelectasis and when IV contrast is contraindicated. PET-CT can significantly improve the target accuracy.137

In patients who receive induction chemotherapy, attempts should be made to obtain a baseline planning CT before induction chemotherapy. If feasible, the initial radiation fields should cover the pre-chemotherapy tumor volume and the cone-down fields should cover the post-chemotherapy tumor volume. However, in patients with compromised lung function or large initial tumor volume, the post-chemotherapy volume can be used to avoid excessive pulmonary toxicity. Photon beam energy should be individualized based on the anatomic location of the tumors and beam angles. In general, photon beam energy between 4 to 10 MV is recommended for beams passing through low-density lung tissue before entering the tumor. For large mediastinal tumors or tumors attached to chest wall, 15 MV or 18 MV energies can be considered for more optimal dose arrangement.

In certain situations when a large volume of normal lung is being irradiated or when tumors are located close to critical structures (i.e., spinal cord), intensity modulated radiotherapy (IMRT) may be considered for high-dose radiation to avoid overdose to normal tissues. A significantly lower risk of radiation pneumonitis and improved overall survival have been observed when using IMRT compared to 3-D conformal RT for lung cancer.138

When IMRT is used, the National Cancer Institute (NCI) IMRT guideline should be followed (http://www.rtog.org/pdf_document/NCI_IMRT_Guidelines_2006.pdf). Under strictly defined protocols, proton therapy may be allowed.139-143

When IMRT and proton therapy are used, daily image guidance at delivery should be used for quality assurance. Use of the modality of image-guided RT (IGRT) should be based on institutional experience and on the treatment accuracy.

Whenever feasible, respiratory motion should be managed. Acceptable methods of accounting for tumor motion, per the AAPM Task Group 76 guideline, include: 1) motion-encompassing methods such as slow CT scanning, inhale and exhale breath-hold CT, four-dimensional (4-D) respiration-correlated CT; 2) respiratory gating methods using an external respiration signal or using internal fiducial markers; 3) breath-hold methods by deep-inspiration breath-hold, active-breathing control (ABC) device, self-held breath-hold without respiratory monitoring; 4) forced shallow breathing with abdominal compression; and 5) real-time tumor-tracking methods.144

Stereotactic Body Radiation Therapy (SBRT) In patients with stage I NSCLC, SBRT provides a statistically significantly higher 5-year survival than 3-D conformal RT.145 SBRT can be considered for inoperable stage I patients with node negative peripheral lesions (see Figure 1) that are less than 5 cm in maximal dimension146-150 or for limited lung metastasis.151,152 SBRT can also be used for brain metastases (see NSCL-11 and section on “Whole Brain Irradiation and SBRT”).153-157 Decisions about whether to recommend SBRT should be based on multidisciplinary discussion.

SBRT fractionation regimens for lung tumors range from one single fraction158 to 3 fractions,149,150 4 fractions,159 and 5 fractions160,161 (see Table 4). Although the optimal number of fractions may be estimated based on the tumor size and total dose,162 an accumulated biological equivalent dose (BED) of 100 Gy or more is associated with better survival.163 The RTOG 0915 trial is currently comparing the outcomes between one single fraction and 4 fractions. SBRT normal tissue dose volume constraints should be strictly followed (see Table 5).




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NCCNRadiofrequency Ablation Studies suggest that radiofrequency ablation (RFA) may be an option for node-negative patients who either refuse surgery or cannot tolerate surgery because of poor PS, significant cardiovascular risk, poor pulmonary function, and/or comorbidities. Optimal candidates for RFA include patients with an isolated peripheral lesion less than 3 cm; RFA can be used for previously irradiated tissue and for palliation.164 A recent study with RFA in 33 patients with NSCLC yielded overall survival of 70% (95% CI, 51%–83%) at 1 year and 48% (30%-65%) at 2 years. Patients with stage I NSCLC (n=13) had a 2-year overall survival of 75% (45%–92%).165

Whole Brain RT and SBRT Many patients with NSCLC have brain metastases (30%-50%), which substantially affect their quality of life.166 Surgery followed by whole brain RT with or without SBRT is a reasonable option for select patients with a single brain metastasis.167,168 Patients with a single brain metastasis who cannot tolerate or refuse surgery may be treated with whole brain RT and/or SBRT.166 Decisions about whether to recommend surgery, whole brain irradiation, SBRT, or combined modality therapy for brain metastases should be based on multidisciplinary discussion, weighing the potential benefit over the risk for each individual patient.

There have been concerns that whole brain RT adversely affects neurocognition. However, a study in 208 patients with brain metastases found that patients who responded (with tumor shrinkage) after whole brain radiation had improved neurocognitive function and that tumor progression affects neurocognition more than whole brain radiation.169 In 132 patients with 1-4 brain metastases who received SBRT with or without whole brain RT, survival was similar in both groups.155 In a subset of 92 of these patients who received SBRT with or without whole brain RT, controlling the brain tumor with combined therapy was more important for stabilizing neurocognitive function.170 However, a study in

58 patients found that patients who received SBRT plus whole brain radiation had fewer CNS recurrences but had worse neurocognition when compared with patients receiving SBRT alone.153

The role of prophylactic cranial irradiation (PCI) is controversial. Although it closed early because of poor accrual, a recent trial (RTOG 0214) of PCI for patients with stage III NSCLC showed that the incidence of brain metastases was decreased in patients who received PCI (18% versus 7.7%) although overall survival was not improved.171 The dose and fractionation of PCI is the same as used for small cell lung cancer (25 Gy in 10 fractions over 2 weeks) (see Small Cell Lung Cancer Guidelines).172

Combined Modality Therapy As previously mentioned, surgery provides the best chance for cure for patients with stage I or stage II disease who are medically fit and can tolerate surgery. In patients with completely resected NSCLC, adjuvant chemotherapy has been shown to improve survival in patients with early-stage disease.173-175 Currently, concurrent chemoradiation appears superior to sequential therapy for patients with unresectable stage III disease.119,176 Surgery is rarely done for patients with stage IV disease. For patients with stage IV disease who have a good PS, platinum-based chemotherapy is beneficial.177-180

Surgery Followed by Chemotherapy The International Adjuvant Lung Cancer Trial (IALT) reported a statistically significant survival benefit with cisplatin-based adjuvant therapy in patients with completely resected stage I, II, or III NSCLC.173 The study included 1867 patients with surgically resected lung cancer who were randomly assigned either to cisplatin-based adjuvant chemotherapy or to observation, with a median follow-up duration of 56 months. A significantly higher survival rate (44.5% versus 40.4% at 5 years; hazard ratio for death, 0.86; 95% confidence interval [CI], 0.76 to




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NCCN0.98; P<.03) and disease-free survival rate (39.4% versus 34.3% at 5 years; hazard ratio, 0.83; 95% CI, 0.74 to 0.94; P<.003) were observed for patients assigned to chemotherapy when compared with observation. IALT data suggest that cisplatin-based adjuvant chemotherapy improves survival 5 years after treatment in patients with completely resected NSCLC. Recent data from the IALT found that after 7.5 years of followup, there were more deaths in the chemotherapy group and that the benefit of chemotherapy decreased over time.181,182 However, data show that adjuvant chemotherapy prevents recurrences.

The NCIC CTG JBR.10 trial and the ANITA (Adjuvant Navelbine International Trialist Association) trial compared the effectiveness of adjuvant vinorelbine plus cisplatin versus observation in early-stage NSCLC. In the JBR.10 trial, 482 patients (ECOG PS of 0-1) with completely resected stage IB (T2, N0) or stage II (T1, N1, or T2, N1) NSCLC were randomly assigned either to vinorelbine plus cisplatin (242 patients) or to observation (240 patients).174 The median age was 61 years in both groups. Chemotherapy was not excessively toxic. Adjuvant chemotherapy significantly prolonged overall survival (94 versus 73 months, hazard ratio for death, 0.69, P=.04) and relapse-free survival (not reached versus 46.7 months, hazard ratio for recurrence, 0.60; P<.001) when compared with observation alone. The 5-year survival rates were 69% and 54%, respectively (P=.03).

However, recent updated data from JBR.10 after 9 years of followup show that when compared with observation alone, adjuvant chemotherapy is beneficial for stage II but not for stage IB patients.183 In stage II patients receiving adjuvant chemotherapy, median survival is 6.8 versus 3.6 years in those who were only observed. Of note, patients receiving chemotherapy did not have an increased death rate. The NCCN guidelines have been revised by deleting certain chemotherapy options for early-stage disease (see UPDATES).

In the ANITA trial, 840 patients (median age, 59 years) with stage IB (T2, N0), II, or IIIA NSCLC were randomly assigned either to adjuvant vinorelbine plus cisplatin or to observation.175 Grade 3/4 toxicities were manageable in the chemotherapy group; however, 7 toxic deaths were reported. After median follow-up of 76 months, median survival was 65.7 months in the chemotherapy group and 43.7 months in the observation group.175 Adjuvant chemotherapy significantly improved the 5-year overall survival in patients with completely resected stage II and IIIA disease, although no benefit was observed in stage I. Some clinicians consider vinorelbine/cisplatin to be the preferred regimen for completely resected early-stage NSCLC based on the number of trials and the amount of use.

A recent meta-analysis in 4,584 patients (the Lung Adjuvant Cisplatin Evaluation) found that postoperative cisplatin-based chemotherapy increased survival over 5 years (absolute benefit of 5.4%); there was no difference among the chemotherapy regimens (vinorelbine, etoposide, others).184 The benefit was greater in patients with stage II and III disease and good performance status.

The CALGB 9633 trial assessed paclitaxel and carboplatin in patients with T2, N0, M0, stage IB lung cancer;185 updated results have been reported.186,187 In this trial, 344 patients (34-81 years) were randomly assigned either to paclitaxel and carboplatin or to observation within 4-8 weeks of resection with a median follow-up duration of 54 months. Adjuvant chemotherapy was well tolerated with no chemotherapy-related toxic deaths. Overall survival at 4 years was not significantly different, although 3-year survival was significant (79% versus 70%, P=.045).186,187 The original results from CALBG suggested that the paclitaxel and carboplatin regimen improved survival in patients with stage I disease; however, the updated results did not show improved survival (although a subset analysis showed a benefit for tumors




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NCCNgreater than 4 cm). Thus, the carboplatin/paclitaxel regimen is only recommended if patients cannot tolerate cisplatin (see NSCL-D).188

Chemoradiation The major controversies in NSCLC relate to the management of patients with stage IIIA disease. All 3 treatment modalities—surgical resection, chemotherapy, and radiation—may be used in treating stage III disease. The ongoing debate centers on which modalities to use and in what sequence.189-193 For patients with unresectable stage IIIA or stage IIIB disease, combined modality therapy (chemoradiation) is superior to radiation alone.189,190,192,193 However, concurrent chemoradiation appears to be superior to sequential therapy.119,176 Concurrent chemoradiation has a higher rate of grade 3 or 4 esophagitis than sequential therapy. For patients with negative margins, most NCCN institutions give sequential chemotherapy followed by RT; for patients with positive margins, most NCCN institutions give concurrent chemo/RT with (or without) chemotherapy). Patient selection affects not only the response to therapy but also how well the patient tolerates therapy.

Concurrent chemoradiation regimens used for initial treatment include cisplatin/etoposide (preferred), cisplatin/vinblastine (preferred), and carboplatin/paclitaxel (category 2B) (see NSCL-E).119,194,195 Other concurrent regimens can also be used, such as cisplatin with gemcitabine, paclitaxel, or vinorelbine.196

A phase II trial from SWOG (9504) assessed concurrent chemoradiation (using cisplatin/etoposide) followed by consolidation docetaxel in 83 patients with unresectable stage IIIB NSCLC.197 Results from SWOG 9504 have shown a median survival of 26 months and a 5-year survival rate of 29%.198 However, results from a phase III trial in patients with unresectable stage III NSCLC assessing consolidation docetaxel after cisplatin/etoposide with concurrent chemoradiation did not show improved survival with docetaxel and did show increased

toxicity.199,200 A randomized controlled trial in 203 unresectable patients with either stage IIIA or IIIB NSCLC assessed induction chemotherapy followed by either radiotherapy alone or chemoradiation using paclitaxel; median survival was 14.1 months versus 18.7 months (P=.091), respectively.201

Chemotherapy For disseminated disease (stage IV) in selected patients with a solitary metastasis, especially a brain metastasis, surgical resection of the metastasis may improve survival.202 Surgical resection of a solitary metastasis located in sites other than the brain remains controversial.

Patients with stage IV disease who have a good PS, benefit from chemotherapy, usually with a platinum-based regimen.177-179 Many drugs are active against stage IV NSCLC. These drugs include the taxanes (paclitaxel, docetaxel), vinorelbine, etoposide, pemetrexed, the camptothecin analogs (irinotecan), and gemcitabine (see NSCL-F). Combinations using many of these drugs produce 1-year survival rates of 30% to 40% and are superior to single agents. Regimens include carboplatin/paclitaxel, cisplatin/paclitaxel, cisplatin/vinorelbine, gemcitabine/cisplatin, cisplatin/pemetrexed, and docetaxel/cisplatin.188,203-206 Phase III randomized trials have shown that many of the platinum-doublet combinations are similar for objective response rates and survival.207,208 The platinum-doublet regimens differ slightly for toxicity, convenience, and cost; thus, clinicians can individualize therapy for their patients. In spite of the development of new chemotherapy regimens, the prognosis for advanced inoperable lung cancer remains poor. Other carboplatin-based regimens include gemcitabine/carboplatin, docetaxel/carboplatin;203,209,210 gemcitabine/docetaxel is another option.211

Note that albumin-bound paclitaxel can be substituted for paclitaxel or docetaxel 1) for patients who have experienced hypersensitivity reactions after receiving paclitaxel or docetaxel despite premedication,




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NCCNor 2) for patients in whom the standard premedications (i.e., dexamethasone, H2 blockers, H1 blockers) are contraindicated.212,213

Specific targeted therapies have been developed for the treatment of advanced lung cancer.214,215 Bevacizumab is a recombinant monoclonal antibody that blocks the vascular endothelial growth factor (VEGF). Erlotinib is a small molecule inhibitor of EGFR. Cetuximab is a monoclonal antibody that targets EGFR.

In 2006, the FDA approved bevacizumab for patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC. The Eastern Cooperative Oncology Group (ECOG) recommends bevacizumab in combination with paclitaxel and carboplatin for select patients with advanced nonsquamous NSCLC based on the results of phase II-III clinical trials (ECOG 4599).216 To receive treatment with bevacizumab and chemotherapy, patients must meet the following criteria: nonsquamous NSCLC and no history of hemoptysis. Any regimen with a high risk for thrombocytopenia—and, therefore, possible bleeding—should be used with caution when combined with bevacizumab.

Erlotinib was approved by FDA in 2004 for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. However, erlotinib can also be given as first-line therapy in patients with advanced or metastatic NSCLC who have known active EGFR mutation or gene amplification (see NSCL-13).31,217-219

A large phase III randomized trial (FLEX) recently assessed cisplatin/vinorelbine with or without cetuximab for patients with advanced NSCLC (most patients had stage IV disease).220 Adding cetuximab slightly increased overall survival (11.3 versus 10.1 months, P = .04).

Maintenance Therapy Maintenance therapy may be given after 4-6 cycles of chemotherapy for patients with tumor response or stable disease who have not progressed. Continuation maintenance refers to the use of at least one of the agents given in first line. Switch maintenance refers to the initiation of a different agent, not included as part of the first-line regimen.

For continuation maintenance therapy, biologic agents (which were initially given in combination with conventional chemotherapy) should be continued until evidence of disease progression or unacceptable toxicity, as per the design of the clinical trials that led to their approval. Bevacizumab (category 1) may be continued beyond 4-6 cycles of initial therapy (i.e., platinum-doublet chemotherapy given with bevacizumab).216,221 Likewise, cetuximab (category 1) may be continued beyond 4-6 cycles of initial therapy (i.e., cisplatin, vinorelbine, and cetuximab therapy).220 Pemetrexed (category 2B) may also be given as continuation maintenance therapy.221 There are no randomized trials supporting the continuation maintenance of conventional cytotoxic agents beyond 4-6 cycles of therapy.

For switch maintenance therapy, 2 recent studies have shown a benefit in progression-free survival and overall survival with the initiation of pemetrexed or erlotinib after first-line chemotherapy (4-6 cycles) in patients without disease progression.222,223 Pemetrexed (category 2B) may be initiated after 4-6 cycles of first-line platinum-doublet chemotherapy, in patients with histologies other than squamous cell carcinoma.222 Erlotinib (category 2B) or docetaxel (category 3) may be initiated after 4-6 cycles of first-line platinum-doublet chemotherapy.223

Initial Clinical Evaluation The NCCN guidelines begin with a patient who has already been given a pathologic diagnosis of NSCLC (see NSCL-1). The clinical stage is




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NCCNinitially determined from disease history (i.e., cough, dyspnea, chest pain, weight loss) and physical examination together with a limited battery of tests, including a pathology review (see NSCL-A), chest CT (including the upper abdomen and adrenals), a complete blood cell (CBC) and platelet count, and chemistry profile. The panel also recommends that smoking cessation counseling be made available to patients (http://www.smokefree.gov/expert.aspx). Based on the initial evaluation, the clinical stage is determined and assigned to one of the pathways that are defined by the stage, specific subdivision of the particular stage, and location of the tumor.

Additional Pretreatment Evaluation Mediastinoscopy As previously noted, evaluation of the mediastinal nodes is a key step in the further staging of the patient. Although PET/CT scans can be used as an initial assessment of the hilar and mediastinal nodes (i.e., the presence of N1, N2, or N3, which are key determinants of stage II and stage III disease), CT scans have known limitations for evaluating the extent of lymph node involvement in lung cancer.224-226

Mediastinoscopy is the gold standard for evaluating mediastinal nodes. Thus, mediastinoscopy is encouraged as part of the initial evaluation, particularly if the results of imaging are not conclusive and the probability of mediastinal involvement is high (based on tumor size and location). Therefore, mediastinoscopy is appropriate for patients with T2-T3 lesions even if the PET/CT scan does not suggest mediastinal node involvement. Mediastinoscopy may also be appropriate to confirm mediastinal node involvement in patients with a positive PET/CT scan. In contrast, because of the low prior probability of lymph node involvement in patients with peripheral T1ab, N0 lesions,227 some NCCN institutions do not use routine mediastinoscopy in these patients (category 2B). However, in patients with peripheral T2a, central T1ab, or T2 lesions with negative PET/CT scans, the risk for mediastinal

lymph node involvement is higher and mediastinoscopy is recommended (see NSCL-2).

Dillemans and colleagues have reported a selective mediastinoscopy strategy, proceeding straight to thoracotomy without mediastinoscopy for T1 peripheral tumors without enlarged mediastinal lymph nodes on preoperative CT.228 This strategy resulted in a 16% incidence of positive N2 nodes discovered only at the time of thoracotomy. For identifying N2 disease, chest CT scans had sensitivity and specificity rates of 69% and 71%, respectively. However, using both the chest CT scan plus mediastinoscopy was significantly more accurate (89% versus 71%) than using the chest CT scan alone for identifying N2 disease. When using CT scans, node positivity is based on the size of the lymph nodes. Therefore, the CT scan will miss small metastases that do not result in node enlargement. To address this issue, Arita and colleagues specifically examined lung cancer metastases to normal size mediastinal lymph nodes in 90 patients and found an incidence of 16% false-negative chest CT scans with histologic identification of occult N2 or N3 disease.229

Bronchoscopy is used in diagnosis and local staging of both central and peripheral lung lesions and is recommended for pretreatment evaluation of stage I, stage II, and stage IIIA tumors. However, in patients who present with a solitary pulmonary nodule where the suspicion of malignancy is high, surgical resection without prior invasive testing may be reasonable.

Other Imaging Studies As previously mentioned, CT scans have known limitations for evaluating the extent of lymph node involvement in lung cancer.224 PET scans have been used to help evaluate the extent of disease and to provide more accurate staging. The NCCN guideline panel reviewed the diagnostic performance of CT and PET scans. Panel members assessed studies that examined the sensitivity and specificity of chest




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NCCNCT scans for mediastinal lymph node staging.230 Depending on the clinical scenario, a sensitivity of 40% to 65% and a specificity of 45% to 90% were reported. Seely and coworkers reported on the number of metastatic lymph nodes discovered on routine mediastinoscopy and chest CT scan in patients with the most favorable tumors (i.e., T1 cancer).231 This study revealed a 21% incidence of identifying N2 or N3 nodes in patients who clinically appeared to have stage IA tumors. The positive predictive value of chest CT scan was only 43% per patient, and the negative predictive value was 92%.

Because they detect tumor physiology, as opposed to anatomy, PET scans may be more sensitive than CT scans. Moreover, if postobstructive pneumonitis is present, there is little correlation between the size of the mediastinal lymph nodes and tumor involvement.232 Chin and colleagues found that PET, when used to stage the mediastinal nodes, was 78% sensitive and 81% specific with a negative predictive value of 89%.233 Kernstine and coworkers compared PET scan to CT scan for identifying N2 and N3 disease in NSCLC.234,235 The PET scan was found to be more sensitive than the CT scan in identifying mediastinal node disease (70% versus 65%). PET/CT has been shown to be useful in restaging patients after adjuvant therapy.236,237

The NCCN panel believes that PET scans can play a role in the evaluation and more accurate staging of NSCLC, for example, in identifying stage I (peripheral and central T1-2, N0), stage II, stage III, and stage IV diseases.238,239 However, PET/CT is even more sensitive and is now recommended by NCCN.240-242 When patients with early-stage disease are accurately staged using PET/CT, inappropriate surgery is avoided.240 However, positive PET/CT scans findings need pathologic or other radiologic confirmation (e.g., MRI of bone). If the PET/CT scan is positive in the mediastinum, the lymph node status needs pathologic confirmation. Precisely how PET/CT scans will fit into

the overall staging and surveillance of NSCLC will become clearer as newer studies mature.

Transesophageal endoscopic ultrasound–guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) have proven useful to stage patients or to diagnose mediastinal lesions; these techniques can be used instead of invasive staging procedures.243 When compared with CT and PET, EBUS-TBNA has a high sensitivity and specificity for staging mediastinal and hilar lymph nodes in patients with lung cancer.244

The routine use of magnetic resonance imaging (MRI) to rule out asymptomatic brain metastases and of bone scans to exclude bone metastases are not recommended. Brain MRI is recommended for patients with stage II, stage III, and stage IV diseases to rule out metastatic disease if aggressive combined-modality therapy is being considered.245

Initial Therapy Stage I, Stage IIA, and Stage IIB (T1-2, N1) Disease It is strongly recommended that determination of tumor resectability be made by board-certified thoracic surgeons who perform lung cancer surgery as a prominent part of their practice. The principles of surgical therapy are listed on NSCL-B.

Depending on the extent and type of comorbidity present, patients with stage I or a subset of stage II (T1–2, N1) tumors are generally candidates for surgical resection and mediastinal node mapping. In some instances, positive mediastinal nodes (N2) are discovered at surgery; in this setting, an additional assessment of staging and tumor resectability must be made, and the treatment (i.e., inclusion of mediastinal lymph node dissection) must be modified accordingly. Therefore, the algorithms include 2 different tracks for T1–3, N2




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NCCNdisease: 1) T1–3, N2 disease discovered unexpectedly at surgical exploration (see NSCL-3); and 2) T1–3, N2 disease confirmed before thoracotomy (see NSCL-6). In the second case, an initial brain MRI and PET/CT scan (if not previously done) are recommended to rule out metastatic disease.

Stage IIB (T3, N0), Stage IIIA, and Stage IIIB Disease For patients with clinical stage IIB (T3, N0) and stage IIIA tumors who have different treatment options (surgery, RT, or chemotherapy), a multidisciplinary evaluation should be performed. For the subsets of stage IIB (T3, N0) and stage IIIA (T3-4, N1) tumors, treatment options are organized according to the location of the tumor (i.e., the superior sulcus, chest wall, and proximal airway or mediastinum). For each location, a determination is made regarding the surgical resectability.

For patients with resectable tumors (T3 invasion, N0-1) in the superior sulcus, the panel suggests concurrent chemoradiation therapy followed by surgical resection and chemotherapy (see NSCL-5). The principles of RT and chemotherapy are listed on NSCL-C and NSCL-D, respectively. For patients with negative margins, most NCCN institutions give sequential chemotherapy and radiation (i.e., chemotherapy followed by RT); for patients with positive margins, most NCCN institutions give concurrent chemoradiation with (or without) chemotherapy. Patients with marginally resectable superior sulcus tumors should undergo concurrent chemoradiation before surgical re-evaluation. For patients with unresectable tumors (T4 extension, N0-1) in the superior sulcus, definitive RT with chemotherapy (i.e., definitive concurrent chemoradiation) is recommended.

In superior sulcus tumors, among the patients treated by surgery and postoperative radiotherapy with or without concurrent chemotherapy, the overall 5-year survival rate has been approximately 40%.246 Neoadjuvant concurrent chemoradiation followed by surgical resection

of a superior sulcus tumor has demonstrated 2-year survival in the 50% to 70% range.111,113,247-249

Surgical resection is the preferred treatment option for patients with tumors of the chest wall, proximal airway, or mediastinum (T3-4, N0-1). Other treatment options include chemotherapy or concurrent chemoradiation before surgical resection.

For patients with stage IIIA disease and positive mediastinal nodes (T1-3, N2), treatment is based on the findings of pathologic mediastinal lymph node evaluation (including mediastinoscopy, mediastinotomy, EBUS-FNA, EUS-FNA, and CT-guided FNA), bronchoscopy, brain MRI, and PET/CT scan; pulmonary function tests (PFTs) should be ordered if not previously done. Patients with negative mediastinal biopsy findings are candidates for surgery, with additional assessment of resectability at the time of thoracotomy. For those patients with resectable lesions, mediastinal lymph node dissection or lymph node sampling should be performed during the surgery. Those individuals found to have unresectable lesions should be treated according to pathologic stage, as defined on NSCL-1. For patients with (T1-2 or T3) node-positive disease, an additional brain MRI and PET/CT scan (if not done previously) are recommended to search for distant metastases. When distant metastases are not present, the panel recommends that the patient be treated with definitive concurrent chemoradiation therapy (see NSCL-7). Although definitive concurrent chemoradiation is recommended (category 1), induction chemotherapy with (or without) RT is another option for patients with T1-3, N2 disease.250 Recommended therapy for metastatic disease is detailed on NSCL-11.

When a lung metastasis is present, it usually occurs in patients with other systemic metastases; the prognosis is poor; therefore, many of these patients are not candidates for surgery. Although uncommon, patients with lung metastases but without systemic metastases have a better prognosis and are candidates for surgery.251 Patients with




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NCCNseparate pulmonary nodule(s) in the same lobe or ipsilateral lung without other systemic metastases are potentially curable by surgery; 5-year survival rates are about 30%.252 Intrapulmonary metastases have been downstaged in the recent TNM revised staging.51,252,253 After surgery, concurrent chemoradiation (if tolerated) is recommended for those with positive margins and chemotherapy is recommended for those with negative margins (see NSCL-8).

The recommended initial treatment options for patients with separate pulmonary nodule(s) in the contralateral lung include surgery, induction chemotherapy before surgery, or induction chemoradiation before surgery (see NSCL-8). For unresectable T4, N0-1 tumors without pleural effusion, concurrent chemoradiation (category 1) is recommended followed by chemotherapy (category 3) (see NSCL-D).198-200 In patients with synchronous nodules (either in contralateral lung or ipsilateral lung), the guidelines suggest treating them as 2 primary lung tumors if both are curable, even if the histology of the 2 tumors is similar (see NSCL-1).

Stage IIIB tumors comprise 2 groups including 1) tumors with contralateral mediastinal nodes (T1-3, N3); and 2) tumors with T4 extension and N2-3 disease, which are unresectable. Surgical resection is not recommended in patients with T1-3, N3 disease. However, in patients with suspected N3 disease, the guidelines recommend pathologic confirmation of nodal status by either mediastinoscopy, supraclavicular lymph node biopsy, thoracoscopy, needle biopsy, mediastinotomy, EUS biopsy, or EBUS) (see NSCL-9).254,255 In addition, PFTs (if not previously done), PET/CT scans, and brain MRI should also be included in the pretreatment evaluation. If these tests are negative, then treatment options for the appropriate nodal status should be followed (see NSCL-1). If these tests are positive, concurrent chemoradiation (category 1) followed by consolidation chemotherapy (category 2B) is recommended.198,200 For metastatic diseases that are

confirmed by PET/CT scan and brain MRI, treatment is detailed on NSCL-11.

For patients with T4 extension, N2-3 disease (stage IIIB), surgical resection is not generally recommended. The initial work-up includes biopsies of the N3 and N2 nodes. If these biopsies are negative, the same treatment options may be used as for stage IIIA (T4, N0-1) disease (see NSCL-8). If either the contralateral or ipsilateral mediastinal node is positive, the patient needs to be treated with concurrent chemoradiation therapy (category 1), although panel members did not all agree that consolidation chemotherapy (category 2B) should be given after chemoradiation (see NSCL-10).198-200

Stage IV Disease Pleural or pericardial effusion is a criterion for stage IV, M1a disease. Note that with the revised staging, T4 with effusion has been reclassified as stage IV, M1a.51 Although pleural effusions are malignant in 90% to 95% of patients, they may be related to obstructive pneumonitis, atelectasis, lymphatic or venous obstruction, or a pulmonary embolus. Therefore, pathologic confirmation of a malignant effusion by using thoracentesis or pericardiocentesis is recommended. In certain cases where thoracentesis is inconclusive, thoracoscopy may be performed. In the absence of nonmalignant causes (e.g., obstructive pneumonia), an exudate or sanguinous effusion is considered malignant no matter what the results of cytologic examination. If the pleural effusion is considered negative, the algorithm tracks back to the confirmed T and N stage (see NSCL-1). However, all pleural effusions, whether malignant or not, are associated with unresectable disease in 95% of cases.256 In patients with effusions that are positive for malignancy, the tumor is treated as M1a with local therapy (i.e., ambulatory small catheter drainage, pleurodesis, and pericardial window) in addition to treatment as for stage IV disease (see NSCL-11).




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NCCNThe algorithm for patients with distant metastases (i.e., stage IV, M1b) depends on the location of the metastases—a solitary nodule in the brain or adrenal—the diagnosis of which is aided by mediastinoscopy, bronchoscopy, PET/CT scan, and brain MRI. The increased sensitivity of PET/CT scans, compared with other imaging methods, may identify additional metastases and, thus, spare some patients from unnecessary surgery. Positive PET/CT scan findings need pathologic or other radiologic confirmation. If the PET/CT scan is positive in the mediastinum, the lymph node status needs pathologic confirmation.

Patients with solitary brain metastases may benefit from surgical resection (see NSCL-11).166 The 5-year survival rates with such an approach range from 10% to 20%;214,257 median survival is about 40 weeks.168 Follow-up whole brain RT (category 1) with or without SBRT (category 2B) may be used.156,169 Stereotactic radiosurgery alone or followed by whole brain radiation is an additional treatment option.155 Such therapy can be effective in patients who have surgically inaccessible brain metastases and in individuals with multiple lesions.258 After their brain lesions are treated, further treatment options for these patients with T1-2, N0-1 or for those with T3, N0 then include 1) surgical resection of the lung lesion followed by chemotherapy (category 2B); 2) SRS (category 2B); or 3) additional chemotherapy followed by surgical resection of the lung lesion (category 2B). Systemic therapy is an option after surgery for patients with higher stage NSCLC (see NSCL-11).

Adrenal metastases from lung cancer are a common occurrence, with approximately 33% of patients having such disease at autopsy. In patients with otherwise resectable primary tumors, however, many solitary adrenal masses are not malignant. Any adrenal mass found on a preoperative CT scan in a patient with lung cancer should be biopsied to rule out benign adenoma. If an adrenal metastasis is found and if the lung lesion is curable, the resection of the adrenal lesion has produced

some long-term survivors (category 3).259,260 However, resection generated major disagreement among the panel members (category 3). Some panel members feel that resection of adrenal glands only makes sense if the synchronous lung disease is stage I or maybe stage II (i.e., resectable). Systemic therapy (see NSCL-13) is another treatment option for adrenal metastasis.

Adjuvant Treatment Chemotherapy or Chemoradiation Treatment options for patients with stage IA (T1ab, N0 disease) and with positive surgical margins (R1, R2) include 1) re-resection (preferred); 2) chemoradiation (category 2B); or 3) RT (category 2B). Patients with T1ab, N0 tumors and with negative surgical margins (R0) are observed. Patients with T2ab, N0 tumors with negative surgical margins are usually observed; chemotherapy (category 2B) is recommended as adjuvant treatment for patients with high-risk features, such as poorly differentiated tumor, vascular invasion, wedge resection, minimal margins, tumors greater than 4 cm, visceral pleural involvement, and Nx (see NSLC-3). If the surgical margins are positive in patients with T2ab, N0 tumors, these patient should have either re-resection with chemotherapy or chemoradiation and chemotherapy.

For patients with T1ab-2ab, N1 or T3, N0 disease and negative surgical margins, the panel recommends 1) chemotherapy (category 1); or 2) chemoradiation (category 3) and chemotherapy for patients with adverse factors (i.e., inadequate mediastinal lymph node dissection, extracapsular spread, multiple positive hilar nodes, and close margins). If surgical margins are positive (T1ab-2ab, N1 or T3, N0), options include: 1) re-resection and chemotherapy; or 2) chemoradiation and chemotherapy.

Patients with T1-3, N2 disease (discovered only at surgical exploration and mediastinal lymph node dissection) and positive margins may be




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NCCNtreated with chemoradiation and chemotherapy (see NSCL-3). Patients with negative margins may be treated with chemotherapy (category 1) and RT.

Panel members disagreed about the use of chemoradiation for stage II disease with negative margins based on the results of the Intergroup E3590 trial.103 In this trial, no difference in survival rates was observed between stage II and stage IIIA patients who had a surgical resection and received either adjuvant radiotherapy alone (median survival = 39 months) or radiotherapy given with concurrent chemotherapy (median survival = 38 months). Because the 5-year survival rate is less than 90%, some NCCN panel members feel that survival rates may increase with newer chemotherapeutic agents and with higher doses of radiation. For example, a phase II trial (RTOG 9705) (n = 88) using concurrent paclitaxel/carboplatin yielded a median survival of 56.3 months with 3-year survival of 61% in patients with resected stage II and IIIA disease.105 A phase II trial in 42 patients had similar results (5-year survival, 68%) except those with adenocarcinoma had poorer survival (only 28%).106 As with stage IB and stage II surgically resected disease, cisplatin-based doublet adjuvant chemotherapy can be used in stage III NSCLC patients who have had surgery (see NSCL-D).

In the case of marginally resectable superior sulcus tumors (T4 extension, N0-1), if the lesion converts to a resectable status following initial treatment, resection is performed and chemotherapy is given (see NSCL-5). If the lesion does not convert (i.e., it remains unresectable), the full course of definitive RT followed by chemotherapy is administered as an adjuvant treatment. Among patients with chest wall lesions with T3 invasion-4 extension, N0-1 disease, those that are initially treated with surgery (preferred) may receive chemotherapy alone if the surgical margins are negative; when surgical margins are positive, they may receive either chemoradiation and chemotherapy or re-resection with chemotherapy. A similar treatment plan is

recommended for resectable tumors of the proximal airway or mediastinum (T3-4, N0-1).

For patients with stage IIIA disease and positive mediastinal nodes (T1-3, N2), if there is no disease progression after initial treatment, patients should be treated with surgery with (or without) chemotherapy (category 2B) (see NSCL-7). In addition, postoperative RT should be given if not used preoperatively. Alternatively, if the disease progresses, patients may be treated with either 1) local therapy using RT (if not given previously) with (or without) chemotherapy, or 2) systemic treatment (see NSCL-11).

In patients with separate pulmonary nodules in the contralateral lung, the option for adjuvant therapy includes surgery, if initial therapy consisted of induction chemotherapy or induction chemoradiation therapy (see NSCL-8). If the margins are negative, observation is usually recommended; another option is adjuvant chemotherapy in select patients with or without RT (if not given previously). If the resection margin is positive, RT is given (if not given previously) followed by chemotherapy.

Because patients with stage III disease have both local and distant failures, theoretically, the use of chemotherapy may eradicate micrometastatic disease obviously present but undetectable at diagnosis. The timing of this chemotherapy varies, with no one clear preference. Such chemotherapy may be given alone, sequentially, or concurrently with RT. In addition, chemotherapy could be given preoperatively or postoperatively in appropriate patients.

On the basis of clinical studies on adjuvant chemotherapy for NSCLC,173-175 the panel has included cisplatin combined with vinorelbine, vinblastine, or etoposide for adjuvant chemotherapy in the guidelines; other options include cisplatin combined with gemcitabine, pemetrexed, or docetaxel (see NSCL-D).188,203,206 For patients with




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NCCNcomorbidities or those who cannot tolerate cisplatin, carboplatin combined with paclitaxel can be used.188

A number of phase II studies have evaluated neoadjuvant chemotherapy for stage III NSCLC, with or without RT, followed by surgery.261-263 Three phase III trials have assessed neoadjuvant chemotherapy followed by surgery compared with surgery alone in the treatment of stage III NSCLC.264-267 The S9900 trial, a SWOG (Southwest Oncology Group) study, one of the largest randomized trials examining preoperative chemotherapy in early-stage NSCLC, assessed surgery alone compared with surgery plus preoperative paclitaxel and carboplatin in patients with stage IB/IIA and stage IIB/IIIA NSCLC (excluding superior sulcus tumors). Progression-free survival and overall survival were in favor of preoperative chemotherapy.266,267 All 3 studies showed a survival advantage for patients who received neoadjuvant chemotherapy. The 2 earlier phase III studies had small number of patients while the SWOG study was stopped early because of the positive results of the IALT study. Induction chemotherapy-surgery approach needs to be compared with induction chemotherapy-RT in large, randomized clinical trials.

Radiation Therapy NCCN panel members disagreed (category 2B) about using RT alone as adjuvant treatment for T1ab, N0 tumors based on a 1998 published report (PORT Meta-analysis Trialists Group, 1998).268 This study showed that postoperative radiotherapy is detrimental to patients with early-stage, completely resected NSCLC and should not be given routinely to such patients. However, the guideline panelists found several flaws in the meta-analysis, including:

Many patients were treated with cobalt 60 equipment, which delivers an inhomogeneous dose distribution;

Studies from the 1960s, when there was no adequate staging, were included in the meta-analysis;

The data analysis lacked detailed timing for postoperative RT; Node-negative NSCLC patients were included (these patients

routinely do not receive postoperative RT); and The meta-analysis included unpublished data.

An assessment of postoperative radiation in 7,465 patients with resected stage II or III NSCLC found that postoperative radiation increased survival in patients with N2 disease but not in those with N1 or N0 disease.269 The ANITA trial also found that postoperative RT increased survival in patients with N2 disease who received adjuvant chemotherapy.104 Adjuvant chemotherapy (category 1) with RT is recommended for T1-3, N2 patients with negative margins (see NSCL-3).

Surveillance and Treatment of Recurrences and Metastases Surveillance The guidelines suggest routine history and physical examinations every 4 to 6 months in the first 2 years and then annually for patients with stages I to IV disease (see NSCL-12). Spiral contrast-enhanced chest CT scan is recommended every 4 to 6 months postoperatively for 2 years (category 2B); a non-contrast-enhanced chest CT is recommended annually thereafter (category 2B), although the panel disagreed about this recommendation.15 PET or brain MRI is not indicated for routine follow-up. Smoking cessation counseling should be provided to aid the treatment of lung cancer and to improve the quality of life of the patients (http://www.smokefree.gov/).

The NCCN guidelines include an algorithm for long-term followup care of NSCLC survivors (see NSCL-G). These recommendations include guidelines for routine cancer surveillance, immunizations, health monitoring, counseling for wellness and health promotion, and cancer screening.




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NCCNTreatment of Recurrences and Distant Metastases Recurrences are subdivided into locoregional recurrences and distant metastases (see NSCL-12). Palliation of symptoms can be achieved with external-beam RT by reducing tumor size. In addition, various regional therapy options are listed for locoregional recurrences. Resectable local recurrence may be managed by re-resection or external-beam RT. For patients with endobronchial obstruction, relieving airway obstruction may increase survival especially in severely compromised patients and may improve the quality of life.270 Obstructed airways can be treated with brachytherapy (endobronchial RT), laser treatment, or endobronchial stent placement; these modalities can be used individually or in combination. In addition, photodynamic therapy (PDT) offers a simple and effective alternative to conventional techniques for palliative debridement of endobronchial obstructions in lung cancer patients.

Mediastinal lymph node recurrence should be treated with concurrent chemoradiation (if RT has not been given previously). For superior venal cava (SVC) obstruction, external-beam RT or stent placement is indicated. For severe hemoptysis, several treatment options are recommended (i.e., external-beam RT, brachytherapy, laser therapy, PDT, surgery, or embolization). Ultimately, surgery may be done to remove the bleeding site. After the treatment for the locoregional recurrence, if no further disseminated disease is evidenced, observation or systemic chemotherapy (category 2B) is recommended. However, for observed disseminated disease, systemic chemotherapy and best supportive care should be applied right away, depending on the performance status (see NSCL-13).

For distant metastases with localized symptoms, diffuse brain metastases, or bony metastasis, palliation of symptoms can be achieved with external-beam RT (see NSCL-12).271 In addition, orthopedic stabilization should be performed if patients are at risk of

fracture, and bisphosphonate therapy should be considered in patients with bone metastasis.272 For other solitary metastasis, the treatment guidelines follow the same pathway as that for stage IV, M1b (solitary site) tumors (see NSCL-11).

In a small subset of patients, recurrence will be suspected only on the basis of positive sputum cytology (see NSCL-16). In this situation, the guidelines recommend further evaluation with bronchoscopy, hematoporphyrin fluorescence, or autofluorescence. If tumor in situ (Tis) is detected, treatment options include endobronchial laser ablation, brachytherapy, photodynamic therapy, and surgical resection. Alternatively, the patient may be re-bronchoscoped every 3 months. If T1-3 tumors are discovered, the algorithms track back to the appropriate clinical stage (see NSCL-1). Surveillance may also detect a new lung primary, and these patients should be treated according to the staging findings.

For recurrent and metastatic disease, first-line therapy includes several options (see NSCL-13) for patients with PS of 0-1: 1) chemotherapy (category 1) (see NSCL-F); 2) bevacizumab in combination with chemotherapy for patients who meet the eligibility criteria; 3) cisplatin and pemetrexed (category 1) for patients who meet the eligibility criteria; 4) cetuximab in combination with vinorelbine and cisplatin(category 2B); or 5) erlotinib for EGFR mutation positive patients. Patients with PS of 2 can receive 1) cetuximab in combination with vinorelbine and cisplatin (category 2B) for patients who meet the eligibility criteria; 2) chemotherapy; or 3) erlotinib for EGFR mutation positive patients (see NSCL-E).

Eligibility criteria for bevacizumab include PS of 0-1, nonsquamous cell histology and no history of hemoptysis. Note that bevacizumab should not be given as a single agent, unless as maintenance if initially used with chemotherapy. Bevacizumab should be given until progression. Any regimen with a high risk for thrombocytopenia and, therefore,




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NCCNpossible bleeding should be used with caution when combined with bevacizumab. Previously patients with brain metastases were excluded from receiving bevacizumab because of concerns about CNS hemorrhage; however, recent data suggest that bevacizumab can be used in patients with treated CNS metastases.273

Eligibility criteria for cisplatin and pemetrexed include PS 0-1, adenocarcinoma or large cell histology (i.e., nonsquamous), and no prior chemotherapy. Panel members disagreed (category 2B) about using cetuximab with cisplatin and vinorelbine, because recent data only showed a slight improvement in survival with the addition of cetuximab (11.3 versus 10.1 months, P = .04).220 Note that full-dose cisplatin for PS 2 patients should be given selectively.

Trial Data In a phase II/III trial (ECOG 4599), 842 patients were randomly assigned to either 1) bevacizumab in combination with paclitaxel and carboplatin; or 2) paclitaxel and carboplatin alone.216,274 Both regimens were well tolerated with selected toxicities. Patients receiving bevacizumab/paclitaxel/carboplatin demonstrated an improved response rate (27% versus 10%, P<.0001), progression-free survival (6.4 versus 4.5 months, P<.0001), and median survival (12.5 versus 10.2 months, P=.0075) when compared to patients receiving paclitaxel and carboplatin alone. The overall 1-year and 2-year survival was 51.9% versus 43.7% and 22.1% versus 16.9%, respectively, in favor of the bevacizumab/paclitaxel/carboplatin arm.216 However, more significant toxicities were observed with bevacizumab/paclitaxel/carboplatin compared to paclitaxel and carboplatin (grade 4 neutropenia: 24% versus 16.4%, grade 3/4 hemorrhage: 4.5% versus 0.7%, hemoptysis: 1.9% versus 0.2%, and hypertension: 6.0% versus 0.7%). Treatment-related deaths were more common with bevacizumab/paclitaxel/carboplatin (9 patients) than with paclitaxel and carboplatin (2 patients). Of interest, a recent trial (AVAil)

comparing cisplatin/gemcitabine with or without bevacizumab did not show an increase in survival with the addition of bevacizumab.275,276

A recent noninferiority trial in 1745 patients with advanced NSCLC (either stage IIIB or IV; most were stage IV) assessed cisplatin plus gemcitabine compared with cisplatin plus pemetrexed.206 Patients with either adenocarcinoma or large cell histology (i.e., nonsquamous) had improved survival with cisplatin/pemetrexed (adenocarcinoma: 12.6 versus 10.9 months). Patients with squamous cell histology had improved survival with the cisplatin/gemcitabine regimen (10.8 versus 9.4 months). When compared with the cisplatin/gemcitabine regimen, the cisplatin/pemetrexed regimen had significantly lower rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P .001); febrile neutropenia (P = .002); and alopecia (P < .001). Treatment-related deaths were similar for both regimens (cisplatin plus pemetrexed, 9 patients [1.0%); cisplatin plus gemcitabine, 6 patients [0.7%]).

In the FLEX trial, 1125 patients with advanced NSCLC (either stage IIIB or IV; most were stage IV) were randomly assigned to either 1) cetuximab in combination with vinorelbine and cisplatin; or 2) vinorelbine and cisplatin alone.220 The response rate was increased with cetuximab (36% versus 29%, P=.012); there was no difference in progression-free survival. Overall survival was significantly better in patients receiving cetuximab (11.3 versus 10.1 months, P=.04). However, there was increased grade 3 or 4 febrile neutropenia in patients receiving cetuximab (22% versus 15%, P<.05); patients also had grade 2 acne-like rash. Treatment-related deaths were similar in both groups (3% versus 2%).

Data show that cisplatin-based combination therapy is superior to best supportive care for patients with advanced, incurable disease. Patients receiving cisplatin-based therapy had an improvement in median survival of 6-12 weeks and a doubling of 1-year survival rates (10%-15% improvement). Cisplatin or carboplatin have been proven effective




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NCCNin combination with any of the following agents: docetaxel, etoposide, gemcitabine, irinotecan, paclitaxel, pemetrexed, vinblastine, and vinorelbine.188,203-206,209,210 New agent/non-platinum regimens are reasonable alternatives if available data show activity and tolerable toxicity (e.g., gemcitabine/docetaxel).211 As yet, there is no evidence that one platinum-based regimen is better than any other.207,208

Maintenance Therapy Patients should be reevaluated for tumor progression with a follow-up CT scan (i.e., after the first or second cycle). Approximately 25% of patients demonstrate disease progression after the initial cycle of chemotherapy. Patients with responsive or stable disease can continue to receive a total of 4 to 6 cycles (preferred) of chemotherapy277 or until the disease progresses. Another option for these patients is continuation maintenance therapy with bevacizumab (category 1), cetuximab (category 1), or pemetrexed (category 2B).216,220 Switch maintenance therapy with pemetrexed (category 2B), erlotinib (category 2B), or docetaxel (category 3) is also an option.222,223 Observation is another option (see NSCL-14). Note that pemetrexed is not recommended for patients with squamous histology.

A recent phase III randomized trial (n = 663) assessed the effect of best supportive care with or without maintenance pemetrexed in patients with advanced NSCLC who had received platinum-based chemotherapy but had not progressed.222 Tumor response (P=.001) and progression-free survival (4.3 versus 2.6 months, P<.0001) were increased in patients who received pemetrexed, especially in patients with adenocarcinoma or large cell histology (i.e., nonsquamous). In patients with nonsquamous histology, preliminary results showed increased overall survival with pemetrexed (15.5 versus 10.3 months, P=.002).

Continuation of Erlotinib or Gefitinib After Progression: Has Its Time Come? Patients may continue to derive benefit from erlotinib or gefitinib after disease progression; discontinuation of erlotinib or gefitinib leads to more rapid progression of disease (symptoms, tumor size, and FDG-avidity on PET scan).278 This strategy mirrors the experience in other oncogene-addicted cancers, particularly HER2-amplified breast cancer. In women with HER2-amplified breast cancer who have had progression of disease on trastuzumab, improved radiographic response rate, time to progression, and overall survival are observed when conventional chemotherapy is added to trastuzumab.279 Data support the continued use of erlotinib or gefitinib in patients with lung adenocarcinoma with EGFR mutations after development of acquired resistance to erlotinib or gefitinib when conventional chemotherapy is initiated.

There is accumulating data about how cancers become resistant to EGFR inhibitors. The most common known mechanism is the acquisition of a secondary mutation in EGFR, T790M, that renders the kinase resistant to erlotinib and gefitinib.280,281 Amplification of the MET oncogene is another validated resistance mechanism. Activation of the IGF-1R pathway has been observed in laboratory models. To overcome all 3 types of resistance, EGFR must still be inhibited. In the case of MET amplification and IGF-IR activation, new inhibitors must be added to the EGFR inhibitor; however, EGFR inhibition is still required to induce remission. Furthermore, data by Riely and colleagues demonstrate that when cancers that were once sensitive to EGFR inhibitors start to progress, discontinuation of the EGFR TKI can lead to a much more accelerated progression of the cancer.278 In total, it is likely that continuing EGFR TKIs is beneficial in many cancers even after they develop resistance to EGFR TKIs.




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NCCNSecond-Line Chemotherapy Although many new active drugs are available for lung cancer, the reported response rates to second-line chemotherapy have generally been less than 10%. Docetaxel, pemetrexed, and erlotinib are recommended as single agent second-line chemotherapy regimens for patients with PS of 0-2 and who have experienced disease progression during or after first-line therapy (see NSCL-15).282-285 Docetaxel has been proven superior to best supportive care, vinorelbine, or ifosfamide with improved survival and quality of life.282,283 When compared with docetaxel, pemetrexed has similar median survival but less toxicity.284,286 Based on recent data, pemetrexed is recommended in patients with adenocarcinoma or large cell histology (i.e., nonsquamous).222 Erlotinib has been proven superior to best supportive care with significantly improved survival and delayed time to symptom deterioration.285

Erlotinib is recommended for second- or third-line therapy for progressive disease in patients with PS of 0-2; erlotinib may be considered for PS 3. Patients receiving erlotinib who have hepatic impairment should be closely monitored during therapy. Erlotinib should be interrupted or discontinued if changes in liver function are severe, such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside the normal range (http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm095059.htm).

In a randomized placebo-controlled double-blind trial (NCIC CTG trial), 731 patients (stage IIIB or IV, PS 0-3) were randomly assigned (2:1) to receive either erlotinib or placebo, following failure of first- or second-line chemotherapy.285 Median age was 61.4 years. The response rate was 8.9% in the erlotinib group and less than 1% in the placebo group (P<.001). Patients treated with erlotinib showed an overall survival of 6.7 versus 4.7 months for placebo (hazard ratio, 0.70; P<.001).

Progression-free survival was 2.2 months for the erlotinib group versus 1.8 months for placebo (hazard ratio, 0.61, adjusted for stratification categories; P<.001). However, 5% of patients discontinued erlotinib because of toxic side effects. This trial confirms that erlotinib can prolong survival in patients after failure of first- or second-line chemotherapy. A randomized phase III trial in 829 patients found that oral topotecan was not inferior to docetaxel.287

If disease progression occurs after second- or third-line chemotherapy, patients with PS of 0-2 may be treated with best supportive care or be enrolled in a clinical trial. Best supportive care only should be provided to patients with PS of 3-4 and progressive disease during any stage of the treatment (see NCCN Palliative Care Guidelines).

Version 2.2010, 03/05/10 © 2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. REF-1



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NCCNReferences

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208. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92-98.

209. Danson S, Middleton MR, O'Byrne KJ, et al. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer. 2003;98:542-553.

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214. Sandler AB, Johnson DH, Herbst RS. Anti-vascular endothelial growth factor monoclonals in non-small cell lung cancer. Clin Cancer Res. 2004;10:4258s-4262s.

215. Giaccone G. Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer. J Clin Oncol. 2005;23:3235-3242.

216. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550.

217. Sequist LV, Joshi VA, Janne PA, et al. Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist. 2007;12:90-98.

218. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957.

219. Inoue A, Kobayashi K, Usui K, et al. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol. 2009;27:1394-1400.

220. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373:1525-1531.

221. Patel JD, Hensing TA, Rademaker A, et al. Phase II Study of Pemetrexed and Carboplatin Plus Bevacizumab With Maintenance Pemetrexed and Bevacizumab As First-Line Therapy for Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2009;27:3284-3289.

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NCCN230. McLoud TC, Bourgouin PM, Greenberg RW, et al. Bronchogenic carcinoma: analysis of staging in the mediastinum with CT by correlative lymph node mapping and sampling. Radiology. 1992;182:319-323.

231. Seely JM, Mayo JR, Miller RR, Muller NL. T1 lung cancer: prevalence of mediastinal nodal metastases and diagnostic accuracy of CT. Radiology. 1993;186:129-132.

232. Kerr KM, Lamb D, Wathen CG, Walker WS, Douglas NJ. Pathological assessment of mediastinal lymph nodes in lung cancer: implications for non-invasive mediastinal staging. Thorax. 1992;47:337-341.

233. Chin R, Jr., Ward R, Keyes JW, et al. Mediastinal staging of non-small-cell lung cancer with positron emission tomography. Am J Respir Crit Care Med. 1995;152:2090-2096.

234. Kernstine KH, Trapp JF, Croft DR, al e. Comparison of positron emission tomography (PET) and computed tomography (CT) to identify N2 and N3 disease in non small cell lung cancer (NSCLC). J Clin Oncol (Meeting Abstracts). 1998;17:458.

235. Kernstine KH, Stanford W, Mullan BF, et al. PET, CT, and MRI with Combidex for mediastinal staging in non-small cell lung carcinoma. Ann Thorac Surg. 1999;68:1022-1028.

236. De Leyn P, Stroobants S, De Wever W, et al. Prospective comparative study of integrated positron emission tomography-computed tomography scan compared with remediastinoscopy in the assessment of residual mediastinal lymph node disease after induction chemotherapy for mediastinoscopy-proven stage IIIA-N2 Non-small-cell lung cancer: a Leuven Lung Cancer Group Study. J Clin Oncol. 2006;24:3333-3339.

237. Cerfolio RJ, Bryant AS, Ojha B. Restaging patients with N2 (stage IIIa) non-small cell lung cancer after neoadjuvant chemoradiotherapy: a prospective study. J Thorac Cardiovasc Surg. 2006;131:1229-1235.

238. Pieterman RM, van Putten JW, Meuzelaar JJ, et al. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med. 2000;343:254-261.

239. Manente P, Vicario G, Piazza F, et al. Does PET/CT modify the therapeutic approach in medical oncology? J Clin Oncol (Meeting Abstracts). 2008;26:17525-.

240. Maziak DE, Darling GE, Inculet RI, et al. Positron emission tomography in staging early lung cancer: a randomized trial. Ann Intern Med. 2009;151:221-228, W-248.

241. Fischer B, Lassen U, Mortensen J, et al. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med. 2009;361:32-39.

242. De Wever W, Stroobants S, Coolen J, Verschakelen JA. Integrated PET/CT in the staging of nonsmall cell lung cancer: technical aspects and clinical integration. Eur Respir J. 2009;33:201-212.

243. Vilmann P, Krasnik M, Larsen SS, Jacobsen GK, Clementsen P. Transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy: a combined approach in the evaluation of mediastinal lesions. Endoscopy. 2005;37:833-839.

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245. Mayr NA, Hussey DH, Yuh WT. Cost-effectiveness of high-contrast-dose MR screening of asymptomatic brain metastasis. AJNR Am J Neuroradiol. 1995;16:215-217.

246. Komaki R, Mountain CF, Holbert JM, et al. Superior sulcus tumors: treatment selection and results for 85 patients without metastasis (Mo) at presentation. Int J Radiat Oncol Biol Phys. 1990;19:31-36.

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254. Pearson FG, DeLarue NC, Ilves R, Todd TR, Cooper JD. Significance of positive superior mediastinal nodes identified at mediastinoscopy in patients with resectable cancer of the lung. J Thorac Cardiovasc Surg. 1982;83:1-11.

255. Rice TW. Thoracoscopy in the staging of thoracic malignancies. In: Kaiser LR, Daniel TM, eds, eds. Thoracoscopic Surgery. Philadelphia: Lippincott Williams & Wilkins; 1993:153-162.

256. Decker DA, Dines DE, Payne WS, Bernatz PE, Pairolero PC. The significance of a cytologically negative pleural effusion in bronchogenic carcinoma. Chest. 1978;74:640-642.

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258. Alexander E, 3rd, Moriarty TM, Davis RB, et al. Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases. J Natl Cancer Inst. 1995;87:34-40.

259. Raviv G, Klein E, Yellin A, Schneebaum S, Ben-Ari G. Surgical treatment of solitary adrenal metastases from lung carcinoma. J Surg Oncol. 1990;43:123-124.

260. Reyes L, Parvez Z, Nemoto T, Regal AM, Takita H. Adrenalectomy for adrenal metastasis from lung carcinoma. J Surg Oncol. 1990;44:32-34.

261. Burkes RL, Ginsberg RJ, Shepherd FA, et al. Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage III unresectable non-small-cell lung cancer: results of the Toronto Phase II Trial. J Clin Oncol. 1992;10:580-586.

262. Bonomi P, Faber L. Neoadjuvant chemoradiation therapy in non-small cell lung cancer: The Rush University experience. Lung Cancer. 1993;9:383-390.

263. Rusch VW, Albain KS, Crowley JJ, et al. Surgical resection of stage IIIA and stage IIIB non-small-cell lung cancer after concurrent induction chemoradiotherapy. A Southwest Oncology Group trial. J Thorac Cardiovasc Surg. 1993;105:97-104; discussion 104-106.

264. Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med. 1994;330:153-158.

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266. Pisters K, Vallieres E, Bunn P, et al. S9900: A phase III trial of surgery alone or surgery plus preoperative (preop) paclitaxel/carboplatin (PC) chemotherapy in early stage non-small cell lung cancer (NSCLC): Preliminary results. J Clin Oncol (Meeting Abstracts). 2005;23:LBA7012-.

267. Pisters K, Vallieres E, Bunn PA, Jr., et al. S9900: Surgery alone or surgery plus induction (ind) paclitaxel/carboplatin (PC) chemotherapy in early stage non-small cell lung cancer (NSCLC): Follow-up on a phase III trial. J Clin Oncol (Meeting Abstracts). 2007;25:7520-.

268. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet. 1998;352:257-263.

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270. Gelb AF, Tashkin DP, Epstein JD, Szeftel A, Fairshter R. Physiologic characteristics of malignant unilateral main-stem bronchial obstruction. Diagnosis and Nd-YAG laser treatment. Am Rev Respir Dis. 1988;138:1382-1385.

271. Chow E, Harris K, Fan G, Tsao M, Sze WM. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol. 2007;25:1423-1436.

272. Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer. 2004;100:2613-2621.

273. Socinski MA, Langer CJ, Huang JE, et al. Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol. 2009;27:5255-5261.

274. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184-2191.

275. Mezger J, von Pawel J, Reck M. Bevacizumab (Bv) single-agent maintenance following Bv-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): Results from an exploratory analysis of the AVAiL study. J Clin Oncol (Meeting Abstracts). 2009;27:e19001-.

276. Reck M, von Pawel J, Zatloukal P, et al. Phase III Trial of Cisplatin Plus Gemcitabine With Either Placebo or Bevacizumab As First-Line Therapy for Nonsquamous Non-Small-Cell Lung Cancer: AVAiL. J Clin Oncol. 2009;27:1227-1234.

277. Socinski MA, Schell MJ, Peterman A, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol. 2002;20:1335-1343.

278. Riely GJ, Kris MG, Zhao B, et al. Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin Cancer Res. 2007;13:5150-5155.

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NCCN281. Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;28 Suppl 1:S24-31.

282. Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000;18:2354-2362.

283. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000;18:2095-2103.

284. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:1589-1597.

285. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123-132.

286. Demarinis F, Paul S, Hanna N, Chang Yao Tsao T, Adachi S, Lim HL. Survival update for the phase III study of pemetrexed vs docetaxel in non-small cell lung cancer (NSCLC). J Clin Oncol (Meeting Abstracts). 2006;24:7133-.

287. Ramlau R, Gervais R, Krzakowski M, et al. Phase III study comparing oral topotecan to intravenous docetaxel in patients with pretreated advanced non-small-cell lung cancer. J Clin Oncol. 2006;24:2800-2807.

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Practice Guidelines in Oncology - Non-Small Cell Lung Cancer